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1
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Yao TT, Chen L, Du Y, Jiang ZY, Cheng Y. MicroRNAs as Regulators, Biomarkers, and Therapeutic Targets in Autism Spectrum Disorder. Mol Neurobiol 2025; 62:5039-5056. [PMID: 39503812 DOI: 10.1007/s12035-024-04582-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 10/22/2024] [Indexed: 03/05/2025]
Abstract
The pathogenesis of autism spectrum disorder (ASD) is complex and is mainly influenced by genetic and environmental factors. Some research has indicated that environmental aspects may interplay with genetic aspects to enhance the risk, and microRNAs (miRNAs) are probably factors in explaining this link between heredity and the environment. MiRNAs are single-stranded noncoding RNAs that can regulate gene expression at the posttranscriptional level. Some research has indicated that miRNAs are closely linked to neurological diseases. Many aberrantly expressed miRNAs have been observed in autism, and these dysregulated miRNAs are expected to be potential biomarkers and provide new strategies for the treatment of this disease. This article reviews the research progress of miRNAs in autism, including their biosynthesis and function. It is found that some miRNAs show aberrant expression patterns in brain tissue and peripheral blood of autistic patients, which may serve as biomarkers of the disease. In addition, the article explores the novel role of exosomes as carriers of miRNAs with the ability to cross the blood-brain barrier and unique expression profiles, offering new possibilities for diagnostic and therapeutic interventions in ASD. The potential of miRNAs in exosomes as diagnostic markers for ASD is specifically highlighted, as well as the prospect of using engineered exosome-encapsulated miRNAs for targeted therapies.
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Affiliation(s)
- Tong-Tong Yao
- Center On Translational Neuroscience, Institute of National Security, Minzu University of China, 27th South Zhongguancun Avenue, Beijing, 100081, China
- School of Ethnology and Sociology, Minzu University of China, Beijing, China
| | - Lei Chen
- Key Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Minzu University of China, Beijing, China
| | - Yang Du
- Key Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Minzu University of China, Beijing, China
| | - Zhong-Yong Jiang
- Department of Medical Laboratory, Affiliated Cancer Hospital of Chengdu Medical College, Chengdu Seventh People's Hospital, Chengdu, China.
| | - Yong Cheng
- Center On Translational Neuroscience, Institute of National Security, Minzu University of China, 27th South Zhongguancun Avenue, Beijing, 100081, China.
- Center On Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China.
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2
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Di Fiore R, Drago-Ferrante R, Suleiman S, Calleja N, Calleja-Agius J. The role of microRNA-9 in ovarian and cervical cancers: An updated overview. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024:108546. [PMID: 39030109 DOI: 10.1016/j.ejso.2024.108546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 07/11/2024] [Indexed: 07/21/2024]
Abstract
Ovarian and cervical cancers are the two most frequent kind of gynaecological cancers (GCs). In spite of advances in prevention, screening and treatment, cervical cancer still leads to an increased morbidity and mortality worldwide. Ovarian cancer is often detected at a late stage, which significantly reduces the effectiveness of available treatments. Therefore, novel methods are desperately needed to improve the clinical care of GC patients. MicroRNAs, also known as short noncoding RNAs (miRNAs/miRs), are a diverse group of RNAs with a length of 22 nucleotides. These typically cause translational repression and mRNA degradation by interacting with target mRNAs' 3' untranslated region (3'-UTR), together with other regions and gene promoters. Under certain conditions, they are also able to activate translation or regulate transcription. It has been demonstrated that miRNAs are crucial to several biological processes leading to tumorigenesis, including GCs. Recent research has shown that miR-9 affects carcinogenesis. In this review, we will provide an overview of current research on the potential utility of miR-9 in the diagnosis, prognosis, and therapy of ovarian and cervical malignancies.
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Affiliation(s)
- Riccardo Di Fiore
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD, 2080, Msida, Malta; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
| | - Rosa Drago-Ferrante
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD, 2080, Msida, Malta; BioDNA Laboratories, Malta Life Sciences Park, SGN, 3000, San Gwann, Malta.
| | - Sherif Suleiman
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD, 2080, Msida, Malta.
| | - Neville Calleja
- Department of Public Health, Faculty of Medicine and Surgery, University of Malta, MSD, 2080, Msida, Malta.
| | - Jean Calleja-Agius
- Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, MSD, 2080, Msida, Malta.
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3
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Ilieva MS. Non-Coding RNAs in Neurological and Neuropsychiatric Disorders: Unraveling the Hidden Players in Disease Pathogenesis. Cells 2024; 13:1063. [PMID: 38920691 PMCID: PMC11201512 DOI: 10.3390/cells13121063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/25/2024] [Accepted: 06/17/2024] [Indexed: 06/27/2024] Open
Abstract
Neurological and neuropsychiatric disorders pose substantial challenges to public health, necessitating a comprehensive understanding of the molecular mechanisms underlying their pathogenesis. In recent years, the focus has shifted toward the intricate world of non-coding RNAs (ncRNAs), a class of RNA molecules that do not encode proteins but play pivotal roles in gene regulation and cellular processes. This review explores the emerging significance of ncRNAs in the context of neurological and neuropsychiatric disorders, shedding light on their diverse functions and regulatory mechanisms. The dysregulation of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), has been implicated in the pathophysiology of conditions such as Alzheimer's disease, Parkinson's disease, schizophrenia, and mood disorders. This review delves into the specific roles these ncRNAs play in modulating key cellular processes, including synaptic plasticity, neuroinflammation, and apoptosis, providing a nuanced understanding of their impact on disease progression. Furthermore, it discusses the potential diagnostic and therapeutic implications of targeting ncRNAs in neurological and neuropsychiatric disorders. The identification of specific ncRNA signatures holds promise for the development of novel biomarkers for early disease detection, while the manipulation of ncRNA expression offers innovative therapeutic avenues. Challenges and future directions in the field are also considered, highlighting the need for continued research to unravel the complexities of ncRNA-mediated regulatory networks in the context of neurological and neuropsychiatric disorders. This review aims to provide a comprehensive overview of the current state of knowledge and stimulate further exploration into the fascinating realm of ncRNAs in the brain's intricate landscape.
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Affiliation(s)
- Mirolyuba Simeonova Ilieva
- The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen N, Ole Maaløes Vej 5, 3rd Floor, 2200 Copenhagen, Denmark
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4
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Huang KY, Upadhyay G, Ahn Y, Sakakura M, Pagan-Diaz GJ, Cho Y, Weiss AC, Huang C, Mitchell JW, Li J, Tan Y, Deng YH, Ellis-Mohr A, Dou Z, Zhang X, Kang S, Chen Q, Sweedler JV, Im SG, Bashir R, Chung HJ, Popescu G, Gillette MU, Gazzola M, Kong H. Neuronal innervation regulates the secretion of neurotrophic myokines and exosomes from skeletal muscle. Proc Natl Acad Sci U S A 2024; 121:e2313590121. [PMID: 38683978 PMCID: PMC11087749 DOI: 10.1073/pnas.2313590121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 03/06/2024] [Indexed: 05/02/2024] Open
Abstract
Myokines and exosomes, originating from skeletal muscle, are shown to play a significant role in maintaining brain homeostasis. While exercise has been reported to promote muscle secretion, little is known about the effects of neuronal innervation and activity on the yield and molecular composition of biologically active molecules from muscle. As neuromuscular diseases and disabilities associated with denervation impact muscle metabolism, we hypothesize that neuronal innervation and firing may play a pivotal role in regulating secretion activities of skeletal muscles. We examined this hypothesis using an engineered neuromuscular tissue model consisting of skeletal muscles innervated by motor neurons. The innervated muscles displayed elevated expression of mRNAs encoding neurotrophic myokines, such as interleukin-6, brain-derived neurotrophic factor, and FDNC5, as well as the mRNA of peroxisome-proliferator-activated receptor γ coactivator 1α, a key regulator of muscle metabolism. Upon glutamate stimulation, the innervated muscles secreted higher levels of irisin and exosomes containing more diverse neurotrophic microRNAs than neuron-free muscles. Consequently, biological factors secreted by innervated muscles enhanced branching, axonal transport, and, ultimately, spontaneous network activities of primary hippocampal neurons in vitro. Overall, these results reveal the importance of neuronal innervation in modulating muscle-derived factors that promote neuronal function and suggest that the engineered neuromuscular tissue model holds significant promise as a platform for producing neurotrophic molecules.
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Affiliation(s)
- Kai-Yu Huang
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Gaurav Upadhyay
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Yujin Ahn
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Chan Zuckerberg Biohub Chicago, Chicago, IL60642
| | - Masayoshoi Sakakura
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Gelson J. Pagan-Diaz
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Younghak Cho
- Department of Chemical and Biomolecular Engineering and KI for the Nano Century, Korea Advanced Institute of Science and Technology, Daejeon305-701, Republic of Korea
| | - Amanda C. Weiss
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Chen Huang
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Jennifer W. Mitchell
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Jiahui Li
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Yanqi Tan
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Yu-Heng Deng
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Austin Ellis-Mohr
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Zhi Dou
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Xiaotain Zhang
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Sehong Kang
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Qian Chen
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Jonathan V. Sweedler
- Chan Zuckerberg Biohub Chicago, Chicago, IL60642
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Sung Gap Im
- Department of Chemical and Biomolecular Engineering and KI for the Nano Century, Korea Advanced Institute of Science and Technology, Daejeon305-701, Republic of Korea
| | - Rashid Bashir
- Chan Zuckerberg Biohub Chicago, Chicago, IL60642
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Hee Jung Chung
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Gabriel Popescu
- Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Martha U. Gillette
- Chan Zuckerberg Biohub Chicago, Chicago, IL60642
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Mattia Gazzola
- Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Hyunjoon Kong
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Chan Zuckerberg Biohub Chicago, Chicago, IL60642
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Korea University-Korea Institute of Science and Technology Graduate School of Converging Science and Technology, Korea University, Seoul02841, Republic of Korea
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5
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Acharya P, Choi NY, Shrestha S, Jeong S, Lee MY. Brain organoids: A revolutionary tool for modeling neurological disorders and development of therapeutics. Biotechnol Bioeng 2024; 121:489-506. [PMID: 38013504 PMCID: PMC10842775 DOI: 10.1002/bit.28606] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 10/03/2023] [Accepted: 11/06/2023] [Indexed: 11/29/2023]
Abstract
Brain organoids are self-organized, three-dimensional (3D) aggregates derived from pluripotent stem cells that have cell types and cellular architectures resembling those of the developing human brain. The current understanding of human brain developmental processes and neurological disorders has advanced significantly with the introduction of this in vitro model. Brain organoids serve as a translational link between two-dimensional (2D) cultures and in vivo models which imitate the neural tube formation at the early and late stages and the differentiation of neuroepithelium with whole-brain regionalization. In addition, the generation of region-specific brain organoids made it possible to investigate the pathogenic and etiological aspects of acquired and inherited brain disease along with drug discovery and drug toxicity testing. In this review article, we first summarize an overview of the existing methods and platforms used for generating brain organoids and their limitations and then discuss the recent advancement in brain organoid technology. In addition, we discuss how brain organoids have been used to model aspects of neurodevelopmental and neurodegenerative diseases, including autism spectrum disorder (ASD), Rett syndrome, Zika virus-related microcephaly, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).
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Affiliation(s)
- Prabha Acharya
- Department of Biomedical Engineering, University of North Texas, Denton, Texas, USA
| | - Na Young Choi
- Department of Biomedical Engineering, University of North Texas, Denton, Texas, USA
- Department of Healthcare Information Technology, Inje University, Gimhae, Republic of Korea
| | - Sunil Shrestha
- Department of Biomedical Engineering, University of North Texas, Denton, Texas, USA
| | - Sehoon Jeong
- Department of Healthcare Information Technology, Inje University, Gimhae, Republic of Korea
| | - Moo-Yeal Lee
- Department of Biomedical Engineering, University of North Texas, Denton, Texas, USA
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6
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Huang L, Lai X, Liang X, Chen J, Yang Y, Xu W, Qin Q, Qin R, Huang X, Xie M, Chen L. A promise for neuronal repair: reprogramming astrocytes into neurons in vivo. Biosci Rep 2024; 44:BSR20231717. [PMID: 38175538 PMCID: PMC10830445 DOI: 10.1042/bsr20231717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/13/2023] [Accepted: 01/02/2024] [Indexed: 01/05/2024] Open
Abstract
Massive loss of neurons following brain injury or disease is the primary cause of central nervous system dysfunction. Recently, much research has been conducted on how to compensate for neuronal loss in damaged parts of the nervous system and thus restore functional connectivity among neurons. Direct somatic cell differentiation into neurons using pro-neural transcription factors, small molecules, or microRNAs, individually or in association, is the most promising form of neural cell replacement therapy available. This method provides a potential remedy for cell loss in a variety of neurodegenerative illnesses, and the development of reprogramming technology has made this method feasible. This article provides a comprehensive review of reprogramming, including the selection and methods of reprogramming starting cell populations as well as the signaling methods involved in this process. Additionally, we thoroughly examine how reprogramming astrocytes into neurons can be applied to treat stroke and other neurodegenerative diseases. Finally, we discuss the challenges of neuronal reprogramming and offer insights about the field.
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Affiliation(s)
- Lijuan Huang
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Xinyu Lai
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Xiaojun Liang
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Jiafeng Chen
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Yue Yang
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Wei Xu
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Qingchun Qin
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Rongxing Qin
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Xiaoying Huang
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Minshan Xie
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Li Chen
- Department of Neurology, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
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7
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Maklad A, Sedeeq M, Chan KM, Gueven N, Azimi I. Exploring Lin28 proteins: Unravelling structure and functions with emphasis on nervous system malignancies. Life Sci 2023; 335:122275. [PMID: 37984514 DOI: 10.1016/j.lfs.2023.122275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 11/07/2023] [Accepted: 11/14/2023] [Indexed: 11/22/2023]
Abstract
Cancer and stem cells share many characteristics related to self-renewal and differentiation. Both cell types express the same critical proteins that govern cellular stemness, which provide cancer cells with the growth and survival benefits of stem cells. LIN28 is an example of one such protein. LIN28 includes two main isoforms, LIN28A and LIN28B, with diverse physiological functions from tissue development to control of pluripotency. In addition to their physiological roles, LIN28A and LIN28B affect the progression of several cancers by regulating multiple cancer hallmarks. Altered expression levels of LIN28A and LIN28B have been proposed as diagnostic and/or prognostic markers for various malignancies. This review discusses the structure and modes of action of the different LIN28 proteins and examines their roles in regulating cancer hallmarks with a focus on malignancies of the nervous system. This review also highlights some gaps in the field that require further exploration to assess the potential of targeting LIN28 proteins for controlling cancer.
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Affiliation(s)
- Ahmed Maklad
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart 7005, Tasmania, Australia
| | - Mohammed Sedeeq
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart 7005, Tasmania, Australia
| | - Kai Man Chan
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart 7005, Tasmania, Australia
| | - Nuri Gueven
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart 7005, Tasmania, Australia
| | - Iman Azimi
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart 7005, Tasmania, Australia; Monash Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton 3168, Victoria, Australia.
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8
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Rizzuti M, Sali L, Melzi V, Scarcella S, Costamagna G, Ottoboni L, Quetti L, Brambilla L, Papadimitriou D, Verde F, Ratti A, Ticozzi N, Comi GP, Corti S, Gagliardi D. Genomic and transcriptomic advances in amyotrophic lateral sclerosis. Ageing Res Rev 2023; 92:102126. [PMID: 37972860 DOI: 10.1016/j.arr.2023.102126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 11/09/2023] [Accepted: 11/10/2023] [Indexed: 11/19/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. ALS shows substantial clinical and molecular heterogeneity. In vitro and in vivo models coupled with multiomic techniques have provided important contributions to unraveling the pathomechanisms underlying ALS. To date, despite promising results and accumulating knowledge, an effective treatment is still lacking. Here, we provide an overview of the literature on the use of genomics, epigenomics, transcriptomics and microRNAs to deeply investigate the molecular mechanisms developing and sustaining ALS. We report the most relevant genes implicated in ALS pathogenesis, discussing the use of different high-throughput sequencing techniques and the role of epigenomic modifications. Furthermore, we present transcriptomic studies discussing the most recent advances, from microarrays to bulk and single-cell RNA sequencing. Finally, we discuss the use of microRNAs as potential biomarkers and promising tools for molecular intervention. The integration of data from multiple omic approaches may provide new insights into pathogenic pathways in ALS by shedding light on diagnostic and prognostic biomarkers, helping to stratify patients into clinically relevant subgroups, revealing novel therapeutic targets and supporting the development of new effective therapies.
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Affiliation(s)
- Mafalda Rizzuti
- Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Luca Sali
- Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Valentina Melzi
- Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Simone Scarcella
- Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan, Italy
| | - Gianluca Costamagna
- Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan, Italy
| | - Linda Ottoboni
- Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan, Italy
| | - Lorenzo Quetti
- Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Lorenzo Brambilla
- Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Federico Verde
- Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan, Italy; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Antonia Ratti
- Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy
| | - Nicola Ticozzi
- Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan, Italy; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Giacomo Pietro Comi
- Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan, Italy; Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefania Corti
- Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan, Italy.
| | - Delia Gagliardi
- Department of Pathophysiology and Transplantation, Dino Ferrari Center, Università degli Studi di Milano, Milan, Italy.
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9
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Rashidi SK, Kalirad A, Rafie S, Behzad E, Dezfouli MA. The role of microRNAs in neurobiology and pathophysiology of the hippocampus. Front Mol Neurosci 2023; 16:1226413. [PMID: 37727513 PMCID: PMC10506409 DOI: 10.3389/fnmol.2023.1226413] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 08/11/2023] [Indexed: 09/21/2023] Open
Abstract
MicroRNAs (miRNAs) are short non-coding and well-conserved RNAs that are linked to many aspects of development and disorders. MicroRNAs control the expression of genes related to different biological processes and play a prominent role in the harmonious expression of many genes. During neural development of the central nervous system, miRNAs are regulated in time and space. In the mature brain, the dynamic expression of miRNAs continues, highlighting their functional importance in neurons. The hippocampus, as one of the crucial brain structures, is a key component of major functional connections in brain. Gene expression abnormalities in the hippocampus lead to disturbance in neurogenesis, neural maturation and synaptic formation. These disturbances are at the root of several neurological disorders and behavioral deficits, including Alzheimer's disease, epilepsy and schizophrenia. There is strong evidence that abnormalities in miRNAs are contributed in neurodegenerative mechanisms in the hippocampus through imbalanced activity of ion channels, neuronal excitability, synaptic plasticity and neuronal apoptosis. Some miRNAs affect oxidative stress, inflammation, neural differentiation, migration and neurogenesis in the hippocampus. Furthermore, major signaling cascades in neurodegeneration, such as NF-Kβ signaling, PI3/Akt signaling and Notch pathway, are closely modulated by miRNAs. These observations, suggest that microRNAs are significant regulators in the complicated network of gene regulation in the hippocampus. In the current review, we focus on the miRNA functional role in the progression of normal development and neurogenesis of the hippocampus. We also consider how miRNAs in the hippocampus are crucial for gene expression mechanisms in pathophysiological pathways.
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Affiliation(s)
- Seyed Khalil Rashidi
- Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Ata Kalirad
- Department of Integrative Evolutionary Biology, Max Planck Institute for Biology Tübingen, Tübingen, Germany
| | - Shahram Rafie
- Department of Neurology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Neuroscience Lab, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ebrahim Behzad
- Department of Neurology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Neuroscience Lab, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mitra Ansari Dezfouli
- Department of Neurology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Neuroscience Lab, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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10
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Vinogradova A, Sysova M, Smirnova P, Sidorova M, Turkin A, Kurilova E, Tuchina O. Enriched Environment Induces Sex-Specific Changes in the Adult Neurogenesis, Cytokine and miRNA Expression in Rat Hippocampus. Biomedicines 2023; 11:1341. [PMID: 37239012 PMCID: PMC10215805 DOI: 10.3390/biomedicines11051341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 04/28/2023] [Accepted: 04/30/2023] [Indexed: 05/28/2023] Open
Abstract
An enriched environment stimulates adult hippocampal plasticity, but the exact cellular and molecular mechanisms are complex, and thus a matter of debate. We studied the behavior and hippocampal neurogenesis in adult male and female Wistar rats that were housed in an enriched environment (EE) for two months. Both EE males and females performed better than control animals in a Barnes maze, meaning that EE enhances spatial memory. However, the expression levels of neurogenesis markers KI67, DCX, Nestin, and Syn1 increased only in EE females, while in EE males only KI67 and BDNF were higher than in the corresponding control. The number of DCX+ neurons on brain slices increased in the dentate gyrus of EE females only, i.e., the level of adult hippocampal neurogenesis was increased in female but not in male rats. The level of anti-inflammatory IL-10 and signaling pathway components was upregulated in EE females. Of 84 miRNAs tested, in the hippocampi of EE female rats we detected upregulation in the expression levels of 12 miRNAs related to neuronal differentiation and morphogenesis, while in EE males four miRNAs were upregulated and involved in the regulation of cell proliferation/differentiation, and one was downregulated and associated with the stimulation of proliferation. Taken altogether, our results point to sex-specific differences in adult hippocampal plasticity, IL-10 expression, and miRNA profiles induced by an enriched environment.
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Affiliation(s)
| | | | | | | | | | | | - Oksana Tuchina
- Educational and Scientific Cluster “Institute of Medicine and Life Sciences (MEDBIO)”, Immanuel Kant Baltic Federal University, 14 A. Nevskogo str., 236016 Kaliningrad, Russia
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11
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Non-coding RNAs as key players in the neurodegenerative diseases: Multi-platform strategies and approaches for exploring the Genome's dark matter. J Chem Neuroanat 2023; 129:102236. [PMID: 36709005 DOI: 10.1016/j.jchemneu.2023.102236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/21/2023] [Accepted: 01/24/2023] [Indexed: 01/26/2023]
Abstract
A growing amount of evidence in the last few years has begun to unravel that non-coding RNAs have a myriad of functions in gene regulation. Intensive investigation on non-coding RNAs (ncRNAs) has led to exploring their broad role in neurodegenerative diseases (NDs) owing to their regulatory role in gene expression. RNA sequencing technologies and transcriptome analysis has unveiled significant dysregulation of ncRNAs attributed to their biogenesis, upregulation, downregulation, aberrant epigenetic regulation, and abnormal transcription. Despite these advances, the understanding of their potential as therapeutic targets and biomarkers underpinning detailed mechanisms is still unknown. Advancements in bioinformatics and molecular technologies have improved our knowledge of the dark matter of the genome in terms of recognition and functional validation. This review aims to shed light on ncRNAs biogenesis, function, and potential role in NDs. Further deepening of their role is provided through a focus on the most recent platforms, experimental approaches, and computational analysis to investigate ncRNAs. Furthermore, this review summarizes and evaluates well-studied miRNAs, lncRNAs and circRNAs concerning their potential role in pathogenesis and use as biomarkers in NDs. Finally, a perspective on the main challenges and novel methods for the future and broad therapeutic use of ncRNAs is offered.
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12
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Almuhayawi MS, Al Jaouni SK, Selim S, Alkhalifah DHM, Marc RA, Aslam S, Poczai P. Integrated Pangenome Analysis and Pharmacophore Modeling Revealed Potential Novel Inhibitors against Enterobacter xiangfangensis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph192214812. [PMID: 36429532 PMCID: PMC9691136 DOI: 10.3390/ijerph192214812] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/24/2022] [Accepted: 10/25/2022] [Indexed: 06/02/2023]
Abstract
Enterobacter xiangfangensis is a novel, multidrug-resistant pathogen belonging to the Enterobacter genus and has the ability to acquire resistance to multiple antibiotic classes. However, there is currently no registered E. xiangfangensis drug on the market that has been shown to be effective. Hence, there is an urgent need to identify novel therapeutic targets and effective treatments for E. xiangfangensis. In the current study, a bacterial pan genome analysis and subtractive proteomics approach was employed to the core proteomes of six strains of E. xiangfangensis using several bioinformatic tools, software, and servers. However, 2611 nonredundant proteins were predicted from the 21,720 core proteins of core proteome. Out of 2611 nonredundant proteins, 372 were obtained from Geptop2.0 as essential proteins. After the subtractive proteomics and subcellular localization analysis, only 133 proteins were found in cytoplasm. All cytoplasmic proteins were examined using BLASTp against the virulence factor database, which classifies 20 therapeutic targets as virulent. Out of these 20, 3 cytoplasmic proteins: ferric iron uptake transcriptional regulator (FUR), UDP-2,3diacylglucosamine diphosphatase (UDP), and lipid-A-disaccharide synthase (lpxB) were chosen as potential drug targets. These drug targets are important for bacterial survival, virulence, and growth and could be used as therapeutic targets. More than 2500 plant chemicals were used to molecularly dock these proteins. Furthermore, the lowest-binding energetic docked compounds were found. The top five hit compounds, Adenine, Mollugin, Xanthohumol C, Sakuranetin, and Toosendanin demonstrated optimum binding against all three target proteins. Furthermore, molecular dynamics simulations and MM/GBSA analyses validated the stability of ligand-protein complexes and revealed that these compounds could serve as potential E. xiangfangensis replication inhibitors. Consequently, this study marks a significant step forward in the creation of new and powerful drugs against E. xiangfangensis. Future studies should validate these targets experimentally to prove their function in E. xiangfangensis survival and virulence.
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Affiliation(s)
- Mohammed S. Almuhayawi
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Soad K. Al Jaouni
- Department of Hematology/Oncology, Yousef Abdulatif Jameel Scientific Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Samy Selim
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia
| | - Dalal Hussien M. Alkhalifah
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Romina Alina Marc
- Food Engineering Department, Faculty of Food Science and Technology, University of Agricultural Science and Veterinary Medicine Cluj-Napoca, 3-5 Calea Mănă ¸stur Street, 400372 Cluj-Napoca, Romania
| | - Sidra Aslam
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Punjab 38000, Pakistan
- Banner Sun Health Research Institute, Sun City, AZ 85351, USA
| | - Peter Poczai
- Botany Unit, Finnish Museum of Natural History, University of Helsinki, P.O. Box 7, FI-00014 Helsinki, Finland
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13
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Tsujimura K, Shiohama T, Takahashi E. microRNA Biology on Brain Development and Neuroimaging Approach. Brain Sci 2022; 12:1366. [PMID: 36291300 PMCID: PMC9599180 DOI: 10.3390/brainsci12101366] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/05/2022] [Accepted: 10/06/2022] [Indexed: 11/22/2022] Open
Abstract
Proper brain development requires the precise coordination and orchestration of various molecular and cellular processes and dysregulation of these processes can lead to neurological diseases. In the past decades, post-transcriptional regulation of gene expression has been shown to contribute to various aspects of brain development and function in the central nervous system. MicroRNAs (miRNAs), short non-coding RNAs, are emerging as crucial players in post-transcriptional gene regulation in a variety of tissues, such as the nervous system. In recent years, miRNAs have been implicated in multiple aspects of brain development, including neurogenesis, migration, axon and dendrite formation, and synaptogenesis. Moreover, altered expression and dysregulation of miRNAs have been linked to neurodevelopmental and psychiatric disorders. Magnetic resonance imaging (MRI) is a powerful imaging technology to obtain high-quality, detailed structural and functional information from the brains of human and animal models in a non-invasive manner. Because the spatial expression patterns of miRNAs in the brain, unlike those of DNA and RNA, remain largely unknown, a whole-brain imaging approach using MRI may be useful in revealing biological and pathological information about the brain affected by miRNAs. In this review, we highlight recent advancements in the research of miRNA-mediated modulation of neuronal processes that are important for brain development and their involvement in disease pathogenesis. Also, we overview each MRI technique, and its technological considerations, and discuss the applications of MRI techniques in miRNA research. This review aims to link miRNA biological study with MRI analytical technology and deepen our understanding of how miRNAs impact brain development and pathology of neurological diseases.
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Affiliation(s)
- Keita Tsujimura
- Department of Radiology, Harvard Medical School, Boston, MA 02115, USA
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129, USA
- Group of Brain Function and Development, Nagoya University Neuroscience Institute of the Graduate School of Science, Nagoya 4648602, Japan
- Research Unit for Developmental Disorders, Institute for Advanced Research, Nagoya University, Nagoya 4648602, Japan
| | - Tadashi Shiohama
- Department of Pediatrics, Chiba University Hospital, Chiba 2608677, Japan
| | - Emi Takahashi
- Department of Radiology, Harvard Medical School, Boston, MA 02115, USA
- Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129, USA
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14
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Chan JNM, Sánchez-Vidaña DI, Anoopkumar-Dukie S, Li Y, Benson Wui-Man L. RNA-binding protein signaling in adult neurogenesis. Front Cell Dev Biol 2022; 10:982549. [PMID: 36187492 PMCID: PMC9523427 DOI: 10.3389/fcell.2022.982549] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/01/2022] [Indexed: 11/13/2022] Open
Abstract
The process of neurogenesis in the brain, including cell proliferation, differentiation, survival, and maturation, results in the formation of new functional neurons. During embryonic development, neurogenesis is crucial to produce neurons to establish the nervous system, but the process persists in certain brain regions during adulthood. In adult neurogenesis, the production of new neurons in the hippocampus is accomplished via the division of neural stem cells. Neurogenesis is regulated by multiple factors, including gene expression at a temporal scale and post-transcriptional modifications. RNA-binding Proteins (RBPs) are known as proteins that bind to either double- or single-stranded RNA in cells and form ribonucleoprotein complexes. The involvement of RBPs in neurogenesis is crucial for modulating gene expression changes and posttranscriptional processes. Since neurogenesis affects learning and memory, RBPs are closely associated with cognitive functions and emotions. However, the pathways of each RBP in adult neurogenesis remain elusive and not clear. In this review, we specifically summarize the involvement of several RBPs in adult neurogenesis, including CPEB3, FXR2, FMRP, HuR, HuD, Lin28, Msi1, Sam68, Stau1, Smaug2, and SOX2. To understand the role of these RBPs in neurogenesis, including cell proliferation, differentiation, survival, and maturation as well as posttranscriptional gene expression, we discussed the protein family, structure, expression, functional domain, and region of action. Therefore, this narrative review aims to provide a comprehensive overview of the RBPs, their function, and their role in the process of adult neurogenesis as well as to identify possible research directions on RBPs and neurogenesis.
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Affiliation(s)
- Jackie Ngai-Man Chan
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | - Dalinda Isabel Sánchez-Vidaña
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- Mental Health Research Centre, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
| | | | - Yue Li
- State Key Laboratory of Component-Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lau Benson Wui-Man
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- Mental Health Research Centre, The Hong Kong Polytechnic University, Hong Kong, Hong Kong SAR, China
- *Correspondence: Lau Benson Wui-Man,
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15
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Baiap3 regulates depressive behaviors in mice via attenuating dense core vesicle trafficking in subsets of prefrontal cortex neurons. Neurobiol Stress 2022; 16:100423. [PMID: 35028340 PMCID: PMC8715124 DOI: 10.1016/j.ynstr.2021.100423] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 12/14/2021] [Accepted: 12/14/2021] [Indexed: 11/21/2022] Open
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are effective first line therapies for treating depression, but are plagued by undesirable side effects and are not effective in all patients. Because SSRIs effectively deplete the neuronal releasable serotonin (5-HT) pool, gaining a deeper understanding of intracellular mechanisms regulating 5-HT pools can help us understand the shortcomings of SSRIs and develop more effective therapies. In this study, we found that BAIAP3 (brain-specific angiogenesis inhibitor 1-associated protein 3) is significantly downregulated in two mouse models of depression (the IR- and CUMS-induced depressive mouse models). In BAIAP3 downregulated models (in vitro and in vivo), we discovered that trafficking of dense core vesicle (DCV), organelles that store, transport and release cargo via exocytosis, was reduced. Accordingly, 5-HT exocytosis and levels in the synapse were lowered, causing defective post-synaptic neurotransmission. In a screen of natural products, we identified eucalyptol, the active components of Eucalyptus, as uniquely capable of increasing neuronal Baiap3 expression and elevate synaptic 5-HT levels. Moreover, eucalyptol treatment relieved depressive behavioral symptoms and restored serotonin levels in mice. Mechanistically, eucalyptol restores Baiap3 expression by reducing inhibitory microRNAs (miR-329, miR-362). These findings illuminate how Baiap3 depletion propagates neurotransmission dysfunction and point to eucalyptol as a novel agent for restoring serotonin exocytosis, suggesting potential for developing eucalyptol as a therapy for treating depression.
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16
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Jalali H, Golchin H, Sadri Z, Karimzadeh Bardei L, Nabiuni M. Selenium enhances the expression of miR-9, miR-124 and miR-29a during neural differentiation of bone marrow mesenchymal stem cells. J Trace Elem Med Biol 2022; 69:126898. [PMID: 34800856 DOI: 10.1016/j.jtemb.2021.126898] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/22/2021] [Accepted: 11/02/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Selenium (Se) is a trace element that plays important role in antioxidant defense in the brain. Sodium selenite (Na2SeO3) is an inorganic salt of Se which has an antioxidant function. In the present study, we investigated the effect of Sodium selenite on the expression of important neuronal microRNAs during neural differentiation of bone marrow-derived stem cells (BMSCs). METHODS Mesenchymal stem cells were collected from rat bone marrow and cultured in the Dulbecco's Modified Eagle Medium (DMEM) medium. 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay was conducted to determine the toxicity of Na2SeO3. For neural induction, BMSCs were divided into control, Na2SeO3 containing (10 ng/mL) and Na2SeO3 free groups and cultured in DMEM medium supplemented with Isobutyl-l-methylxanthine (IBMX), Fibroblast growth factor 2 (FGF2), B27, Retinoic acid, and brain derived neurotrophic factor (BDNF) for 14 days. At the end of the differentiation, immunostaining against Microtubule associated protein 2 (Map-2) and Choline acetyltransferase (ChAT) proteins was performed. Also, the total RNA is extracted from control and neural differentiated cells using a special kit, and the expression of miR-9, miR-124, and miR-29a was analyzed using real-time polymerase chain reaction (RT-PCR). RESULTS Increasing Na2SeO3 concentrations had increasing toxicity; therefore, the concentration of 10 ng/mL was used as a supplement during neural differentiation. Examination of the expression of Map-2 and ChAT proteins showed that Na2SeO3 increased the expression of them and consequently the neuronal differentiation of BMSCs. Na2SeO3 also significantly increased the expression of miR-9, miR-124, and miR-29a in BMSCs undergoing neuronal differentiation. CONCLUSIONS Our results suggest that the protective effect of selenium on neural differentiation of stem cells may be mediated through neuron specific microRNAs. This result further highlights the importance of selenium supplementation in preventing neuronal diseases.
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Affiliation(s)
- Hanieh Jalali
- Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, No. 43, South Moffateh Ave., Tehran, 15719-14911, Iran.
| | - Hasti Golchin
- Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, No. 43, South Moffateh Ave., Tehran, 15719-14911, Iran.
| | - Zahra Sadri
- Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, No. 43, South Moffateh Ave., Tehran, 15719-14911, Iran.
| | - Latifeh Karimzadeh Bardei
- School of Biology, College of Science, University of Tehran, Engelab Ave., Tehran, 14155-6655, Iran.
| | - Mohammad Nabiuni
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, No. 43, South Moffateh Ave., Tehran, 15719-14911, Iran.
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17
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Roumans S, Sundquist K, Memon AA, Hedelius A, Sundquist J, Wang X. Association of circulating let-7b-5p with major depressive disorder: a nested case-control study. BMC Psychiatry 2021; 21:616. [PMID: 34886843 PMCID: PMC8662878 DOI: 10.1186/s12888-021-03621-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/22/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Major depressive disorder (MDD) is one of the most common psychiatric disorders and is a great disease burden. However, its underlying pathophysiology and aetiology remain poorly understood. Available evidence suggests that circulating microRNAs (miRNAs) are associated with MDD, but it is still unknown whether miRNAs can predict subsequent incident MDD. METHODS In this nested case-control study, a total of 104 individuals, who were free of MDD at baseline, from the Women's Health in Lund Area (WHILA) cohort were included. Among them, 52 individuals developed MDD (cases) during the 5 years follow-up and 52 individuals did not develop MDD (controls). Plasma expression levels of miR-17-5p, miR-134-5p, miR-144-5p, let-7b-5p and let-7c-5p at baseline were assessed using qRT-PCR. Logistic regression was used to estimate the odds of developing MDD among individuals with different levels of miRNA expression. RESULTS Plasma expression levels of let-7b-5p were significantly lower (p = 0.02) at baseline in cases compared to controls. After adjustment for age and BMI, let-7b-5p was negatively associated with odds for developing MDD (OR = 0.33, p = 0.03, 95% CI = 0.12-0.91). Moreover, let-7b-5p expression levels showed a trend over time with larger differences between cases and controls for the earlier cases (MDD diagnosis <2 years from baseline) than MDD cases developed later (MDD diagnosis 2-5 years from baseline). CONCLUSIONS These findings show that lower plasma levels of let-7b-5p are associated with a higher future risk of MDD. Results need to be validated in a large cohort to examine its potential as a peripheral biomarker for MDD.
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Affiliation(s)
- Sanne Roumans
- grid.4514.40000 0001 0930 2361Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
| | - Kristina Sundquist
- grid.4514.40000 0001 0930 2361Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden ,grid.59734.3c0000 0001 0670 2351Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, USA ,grid.411621.10000 0000 8661 1590Center for Community-based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Matsue, Japan
| | - Ashfaque A. Memon
- grid.4514.40000 0001 0930 2361Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
| | - Anna Hedelius
- grid.4514.40000 0001 0930 2361Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
| | - Jan Sundquist
- grid.4514.40000 0001 0930 2361Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden ,grid.59734.3c0000 0001 0670 2351Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, USA ,grid.411621.10000 0000 8661 1590Center for Community-based Healthcare Research and Education (CoHRE), Department of Functional Pathology, School of Medicine, Shimane University, Matsue, Japan
| | - Xiao Wang
- Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden. .,Center for Primary Health Care Research, Wallenberg Laboratory, Inga-Marie Nilssons gata 53, plan 6 Box 50332, 202 13, Malmö, Sweden.
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Morello G, Villari A, Spampinato AG, La Cognata V, Guarnaccia M, Gentile G, Ciotti MT, Calissano P, D’Agata V, Severini C, Cavallaro S. Transcriptional Profiles of Cell Fate Transitions Reveal Early Drivers of Neuronal Apoptosis and Survival. Cells 2021; 10:3238. [PMID: 34831459 PMCID: PMC8620386 DOI: 10.3390/cells10113238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/12/2021] [Accepted: 11/17/2021] [Indexed: 11/23/2022] Open
Abstract
Neuronal apoptosis and survival are regulated at the transcriptional level. To identify key genes and upstream regulators primarily responsible for these processes, we overlayed the temporal transcriptome of cerebellar granule neurons following induction of apoptosis and their rescue by three different neurotrophic factors. We identified a core set of 175 genes showing opposite expression trends at the intersection of apoptosis and survival. Their functional annotations and expression signatures significantly correlated to neurological, psychiatric and oncological disorders. Transcription regulatory network analysis revealed the action of nine upstream transcription factors, converging pro-apoptosis and pro-survival-inducing signals in a highly interconnected functionally and temporally ordered manner. Five of these transcription factors are potential drug targets. Transcriptome-based computational drug repurposing produced a list of drug candidates that may revert the apoptotic core set signature. Besides elucidating early drivers of neuronal apoptosis and survival, our systems biology-based perspective paves the way to innovative pharmacology focused on upstream targets and regulatory networks.
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Affiliation(s)
- Giovanna Morello
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), Via Paolo Gaifami, 18, 95125 Catania, Italy; (G.M.); (A.V.); (A.G.S.); (V.L.C.); (M.G.); (G.G.)
| | - Ambra Villari
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), Via Paolo Gaifami, 18, 95125 Catania, Italy; (G.M.); (A.V.); (A.G.S.); (V.L.C.); (M.G.); (G.G.)
| | - Antonio Gianmaria Spampinato
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), Via Paolo Gaifami, 18, 95125 Catania, Italy; (G.M.); (A.V.); (A.G.S.); (V.L.C.); (M.G.); (G.G.)
| | - Valentina La Cognata
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), Via Paolo Gaifami, 18, 95125 Catania, Italy; (G.M.); (A.V.); (A.G.S.); (V.L.C.); (M.G.); (G.G.)
| | - Maria Guarnaccia
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), Via Paolo Gaifami, 18, 95125 Catania, Italy; (G.M.); (A.V.); (A.G.S.); (V.L.C.); (M.G.); (G.G.)
| | - Giulia Gentile
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), Via Paolo Gaifami, 18, 95125 Catania, Italy; (G.M.); (A.V.); (A.G.S.); (V.L.C.); (M.G.); (G.G.)
| | - Maria Teresa Ciotti
- Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Via E. Ramarini, 32, Monterotondo Scalo, 00015 Rome, Italy; (M.T.C.); (C.S.)
| | - Pietro Calissano
- European Brain Research Institute (EBRI Foundation), Viale Regina Elena, 295, 00161 Rome, Italy;
| | - Velia D’Agata
- Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Via Santa Sofia, 87, 95123 Catania, Italy;
| | - Cinzia Severini
- Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Via E. Ramarini, 32, Monterotondo Scalo, 00015 Rome, Italy; (M.T.C.); (C.S.)
| | - Sebastiano Cavallaro
- Institute for Biomedical Research and Innovation, National Research Council (IRIB-CNR), Via Paolo Gaifami, 18, 95125 Catania, Italy; (G.M.); (A.V.); (A.G.S.); (V.L.C.); (M.G.); (G.G.)
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Zeidler M, Kummer KK, Schöpf CL, Kalpachidou T, Kern G, Cader MZ, Kress M. NOCICEPTRA: Gene and microRNA Signatures and Their Trajectories Characterizing Human iPSC-Derived Nociceptor Maturation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2102354. [PMID: 34486248 PMCID: PMC8564443 DOI: 10.1002/advs.202102354] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Indexed: 05/07/2023]
Abstract
Nociceptors are primary afferent neurons serving the reception of acute pain but also the transit into maladaptive pain disorders. Since native human nociceptors are hardly available for mechanistic functional research, and rodent models do not necessarily mirror human pathologies in all aspects, human induced pluripotent stem cell-derived nociceptors (iDN) offer superior advantages as a human model system. Unbiased mRNA::microRNA co-sequencing, immunofluorescence staining, and qPCR validations, reveal expression trajectories as well as miRNA target spaces throughout the transition of pluripotent cells into iDNs. mRNA and miRNA candidates emerge as regulatory hubs for neurite outgrowth, synapse development, and ion channel expression. The exploratory data analysis tool NOCICEPTRA is provided as a containerized platform to retrieve experimentally determined expression trajectories, and to query custom gene sets for pathway and disease enrichments. Querying NOCICEPTRA for marker genes of cortical neurogenesis reveals distinct similarities and differences for cortical and peripheral neurons. The platform provides a public domain neuroresource to exploit the entire data sets and explore miRNA and mRNA as hubs regulating human nociceptor differentiation and function.
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Affiliation(s)
- Maximilian Zeidler
- Institute of PhysiologyMedical University of InnsbruckInnsbruck6020Austria
| | - Kai K. Kummer
- Institute of PhysiologyMedical University of InnsbruckInnsbruck6020Austria
| | - Clemens L. Schöpf
- Institute of PhysiologyMedical University of InnsbruckInnsbruck6020Austria
| | | | - Georg Kern
- Institute of PhysiologyMedical University of InnsbruckInnsbruck6020Austria
| | - M. Zameel Cader
- Weatherall Institute of Molecular MedicineUniversity of OxfordOxfordOX3 9DSUK
| | - Michaela Kress
- Institute of PhysiologyMedical University of InnsbruckInnsbruck6020Austria
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Nandakumar S, Shahani P, Datta I, Pal R. Interventional Strategies for Parkinson Disease: Can Neural Precursor Cells Forge a Path Ahead? ACS Chem Neurosci 2021; 12:3785-3794. [PMID: 34628850 DOI: 10.1021/acschemneuro.1c00525] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Neural precursor cells (NPCs), derived from pluripotent stem cells (PSCs), with their unique ability to generate multiple neuronal and glial cell types are extremely useful for understanding biological mechanisms in normal and diseased states. However, generation of specific neuronal subtypes (mature) from NPCs in large numbers adequate for cell therapy is challenging due to lack of a thorough understanding of the cues that govern their differentiation. Interestingly, neural stem cells (NSCs) themselves are in consideration for therapy given their potency to form different neural cell types, release of trophic factors, and immunomodulatory effects that confer neuroprotection. With the recent COVID-19 outbreak and its accompanying neurological indications, the immunomodulatory role of NSCs may gain additional significance in the prevention of disease progression in vulnerable populations. In this regard, small-molecule mediated NPC generation from PSCs via NSC formation has become an important strategy that ensures consistency and robustness of the process. The development of the mammalian brain occurs along the rostro-caudal axis, and the establishment of anterior identity is an early event. Wnt signaling, along with fibroblast growth factor and retinoic acid, acts as a caudalization signal. Further, the increasing amount of epigenetic data available from human fetal brain development has enhanced both our understanding of and ability to experimentally manipulate these developmental regulatory programs in vitro. However, the impact on homing and engraftment after transplantation and subsequently on therapeutic efficacy of NPCs based on their derivation strategy is not yet clear. Another formidable challenge in cell replacement therapy for neurodegenerative disorders is the mode of delivery. In this Perspective, we discuss these core ideas with insights from our preliminary studies exploring the role of PSC-derived NPCs in rat models of MPTP-induced Parkinson's disease following intranasal injections.
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Affiliation(s)
- Swapna Nandakumar
- Eyestem Research, Centre for Cellular and Molecular Platforms (C-CAMP), Bengaluru 560065, Karnataka, India
| | - Pradnya Shahani
- Department of Biophysics, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru 560029, Karnataka, India
| | - Indrani Datta
- Department of Biophysics, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru 560029, Karnataka, India
| | - Rajarshi Pal
- Eyestem Research, Centre for Cellular and Molecular Platforms (C-CAMP), Bengaluru 560065, Karnataka, India
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21
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Vasan L, Park E, David LA, Fleming T, Schuurmans C. Direct Neuronal Reprogramming: Bridging the Gap Between Basic Science and Clinical Application. Front Cell Dev Biol 2021; 9:681087. [PMID: 34291049 PMCID: PMC8287587 DOI: 10.3389/fcell.2021.681087] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/02/2021] [Indexed: 12/15/2022] Open
Abstract
Direct neuronal reprogramming is an innovative new technology that involves the conversion of somatic cells to induced neurons (iNs) without passing through a pluripotent state. The capacity to make new neurons in the brain, which previously was not achievable, has created great excitement in the field as it has opened the door for the potential treatment of incurable neurodegenerative diseases and brain injuries such as stroke. These neurological disorders are associated with frank neuronal loss, and as new neurons are not made in most of the adult brain, treatment options are limited. Developmental biologists have paved the way for the field of direct neuronal reprogramming by identifying both intrinsic cues, primarily transcription factors (TFs) and miRNAs, and extrinsic cues, including growth factors and other signaling molecules, that induce neurogenesis and specify neuronal subtype identities in the embryonic brain. The striking observation that postmitotic, terminally differentiated somatic cells can be converted to iNs by mis-expression of TFs or miRNAs involved in neural lineage development, and/or by exposure to growth factors or small molecule cocktails that recapitulate the signaling environment of the developing brain, has opened the door to the rapid expansion of new neuronal reprogramming methodologies. Furthermore, the more recent applications of neuronal lineage conversion strategies that target resident glial cells in situ has expanded the clinical potential of direct neuronal reprogramming techniques. Herein, we present an overview of the history, accomplishments, and therapeutic potential of direct neuronal reprogramming as revealed over the last two decades.
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Affiliation(s)
- Lakshmy Vasan
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Eunjee Park
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Luke Ajay David
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Taylor Fleming
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
| | - Carol Schuurmans
- Sunnybrook Research Institute, Biological Sciences Platform, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
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22
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Wang M, Bai Y, Chi H, Lin P, Wu Y, Cui J, Wang Y, Sun J, Lang MF. miR-451 protects against ischemic stroke by targeting Phd3. Exp Neurol 2021; 343:113777. [PMID: 34058227 DOI: 10.1016/j.expneurol.2021.113777] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 05/10/2021] [Accepted: 05/27/2021] [Indexed: 12/19/2022]
Abstract
Ischemic stroke still remains a therapeutic challenge due to its complex pathogenesis and implications. By screening biomarkers in the peripheral blood of ischemic stroke patients, miR-451 was identified as a differentially expressed miRNA along the disease course of ischemic stroke. To investigate the role of miR-451, middle cerebral artery occlusion (MCAO) was performed as an ischemic stroke model in mice. Intracerebroventricular administration of miR-451 mimic in the MCAO mice significantly decreased infarct size, while miR-451 inhibitor significantly increased infarct size. To understand the molecular mechanism of the protective effect of miR-451, Phd3 (also Egln3) was validated as a new miR-451 target. Either fewer or more Phd3-positive cells were observed in brain sections from mice receiving miR-451 mimic or inhibitor, respectively. In addition, the levels of p53 (a known Phd3 target) were significantly downregulated when the levels of Phd3 were reduced, suggesting its participation in reducing apoptosis after the miR-451 administration. Indeed, reduced apoptosis upon miR-451 mimic administration was detected by TUNEL staining. In conclusion, this study demonstrated a new protective role of miR-451 in cerebral ischemia and identified Phd3 as a novel miR-451 target, linking the mechanism to the involvement of p53 in the regulation of apoptosis during the pathogenesis of ischemic stroke.
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Affiliation(s)
- Mengmeng Wang
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China; Medical College, Institute of Microanalysis, Dalian University, Dalian, Liaoning 116622, China; Graduate School, Dalian University, Dalian, Liaoning 116622, China
| | - Ying Bai
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China.
| | - Haitao Chi
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China
| | - Ping Lin
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China
| | - Yu Wu
- Medical College, Institute of Microanalysis, Dalian University, Dalian, Liaoning 116622, China
| | - Jiahui Cui
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China
| | - Yi Wang
- Department of Neurology, Dalian University Affiliated Xinhua Hospital, Dalian, Liaoning 116021, China
| | - Jing Sun
- College of Environmental and Chemical Engineering, Institute of Microanalysis, Dalian University, Dalian, Liaoning 116622, China
| | - Ming-Fei Lang
- Medical College, Institute of Microanalysis, Dalian University, Dalian, Liaoning 116622, China.
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23
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Yapijakis C. Regulatory Role of MicroRNAs in Brain Development and Function. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1195:237-247. [PMID: 32468482 DOI: 10.1007/978-3-030-32633-3_32] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules of about 20-22 nucleotides. After their posttranscriptional maturation, miRNAs are loaded into the ribonucleoprotein complex RISC and modulate gene expression by binding to the 3' untranslated region of their target mRNAs through base-pairing, which in turn triggers mRNA degradation or translational inhibition. There is mounting evidence that miRNAs regulate various biological processes, including cell proliferation, differentiation, and apoptosis. Several studies have shown that miRNAs play an important role in neurogenesis and brain development.This review discusses recent progress on understanding the implication of precisely regulated miRNA expression in normal brain development and function. In addition, it reports known cases of dysregulation of miRNA expression and function implicated in the pathogenesis of neurodevelopmental disorders, craniofacial dysmorphic syndromes, neurodegenerative diseases, and psychiatric disorders. Current knowledge regarding the role of miRNAs in the brain in conjunction with the complex interplay between genetic and epigenetic factors are discussed.
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Affiliation(s)
- Christos Yapijakis
- 1st Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, "Haghia Sophia" Hospital, Athens, Greece. .,Department of Molecular Genetics, Cephalogenetics Diagnostic Center, Athens, Greece.
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24
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Charrout M, Reinders MJT, Mahfouz A. Untangling biological factors influencing trajectory inference from single cell data. NAR Genom Bioinform 2020; 2:lqaa053. [PMID: 33575604 PMCID: PMC7671373 DOI: 10.1093/nargab/lqaa053] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/17/2020] [Accepted: 07/07/2020] [Indexed: 12/14/2022] Open
Abstract
Advances in single-cell RNA sequencing over the past decade has shifted the discussion of cell identity toward the transcriptional state of the cell. While the incredible resolution provided by single-cell RNA sequencing has led to great advances in unraveling tissue heterogeneity and inferring cell differentiation dynamics, it raises the question of which sources of variation are important for determining cellular identity. Here we show that confounding biological sources of variation, most notably the cell cycle, can distort the inference of differentiation trajectories. We show that by factorizing single cell data into distinct sources of variation, we can select a relevant set of factors that constitute the core regulators for trajectory inference, while filtering out confounding sources of variation (e.g. cell cycle) which can perturb the inferred trajectory. Script are available publicly on https://github.com/mochar/cell_variation.
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Affiliation(s)
- Mohammed Charrout
- Delft Bioinformatics Lab, Delft University of Technology, Delft 2628 XE, The Netherlands
- Leiden Computational Biology Center, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands
| | - Marcel J T Reinders
- Delft Bioinformatics Lab, Delft University of Technology, Delft 2628 XE, The Netherlands
- Leiden Computational Biology Center, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands
| | - Ahmed Mahfouz
- Delft Bioinformatics Lab, Delft University of Technology, Delft 2628 XE, The Netherlands
- Leiden Computational Biology Center, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands
- Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands
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25
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Liu X, Fan B, Chopp M, Zhang Z. Epigenetic Mechanisms Underlying Adult Post Stroke Neurogenesis. Int J Mol Sci 2020; 21:E6179. [PMID: 32867041 PMCID: PMC7504398 DOI: 10.3390/ijms21176179] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 08/24/2020] [Accepted: 08/25/2020] [Indexed: 12/15/2022] Open
Abstract
Stroke remains the leading cause of adult disability. Post-stroke neurogenesis contributes to functional recovery. As an intrinsic neurorestorative process, it is important to elucidate the molecular mechanism underlying stroke-induced neurogenesis and to develop therapies designed specifically to augment neurogenesis. Epigenetic mechanisms include DNA methylation, histone modification and its mediation by microRNAs and long-non-coding RNAs. In this review, we highlight how epigenetic factors including DNA methylation, histone modification, microRNAs and long-non-coding RNAs mediate stroke-induced neurogenesis including neural stem cell self-renewal and cell fate determination. We also summarize therapies targeting these mechanisms in the treatment of stroke.
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Affiliation(s)
- Xianshuang Liu
- Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA; (B.F.); (M.C.); (Z.Z.)
| | - Baoyan Fan
- Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA; (B.F.); (M.C.); (Z.Z.)
| | - Michael Chopp
- Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA; (B.F.); (M.C.); (Z.Z.)
- Department of Physics, Oakland University, Rochester, MI 48309, USA
| | - Zhenggang Zhang
- Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA; (B.F.); (M.C.); (Z.Z.)
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26
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Su X, Gu X, Zhang Z, Li W, Wang X. Retinoic acid receptor gamma is targeted by microRNA-124 and inhibits neurite outgrowth. Neuropharmacology 2020; 163:107657. [PMID: 31170403 DOI: 10.1016/j.neuropharm.2019.05.034] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 05/02/2019] [Accepted: 05/29/2019] [Indexed: 12/18/2022]
Abstract
During brain development, neurite outgrowth is required for brain development and is regulated by many factors. All-trans retinoic acid (RA) is an important regulator of cell growth and differentiation. MicroRNA-124 (miR-124), a brain-specific microRNA, has been implicated in stimulating neurite growth. In this study, we found that retinoic acid receptor gamma (RARG) expression was decreased, whereas miR-124 expression was increased during neural differentiation in mouse Neuroblastoma (N2a) Cells, P19 embryonal carcinoma (P19) cells, and mouse brain, as detected by immunoblotting or RT-qPCR. And we proved that miR-124 inhibited RARG expression by binding to the 3' UTR of RARG with a luciferase reporter assay. Upregulation of miR-124 (using miR-124 overexpressing plasmid and miR-124 mimic) led to a significant decrease in RARG protein in N2a cells and primary neurons. Therefore, we asked whether and how the miR-124/RARG axis regulates neuronal outgrowth, which is poorly understood. Strikingly, RARG knockdown by shRNA stimulated neurite growth in N2a cells and primary neurons, whereas RARG overexpression (without 3' UTR) inhibited neurite growth in N2a cells, P19 cells, and primary neurons. Furthermore, RARG knockdown could partially eliminate neurite outgrowth defects caused by the inhibitor of miR-124, while RARG overexpression could reverse the neurite outgrowth enhancing effect of the upregulation of miR-124. Collectively, the data reveal that miR-124/RARG axis is critical for neurite outgrowth. RARG emerges as a new target regulated by miR-124 that modulates neurite outgrowth, providing a novel context in which these two molecules function.
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Affiliation(s)
- Xiaohong Su
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xi Gu
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhiduo Zhang
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Weipeng Li
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xuemin Wang
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
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27
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Wu C, Zhang X, Chen P, Ruan X, Liu W, Li Y, Sun C, Hou L, Yin B, Qiang B, Shu P, Peng X. MicroRNA-129 modulates neuronal migration by targeting Fmr1 in the developing mouse cortex. Cell Death Dis 2019; 10:287. [PMID: 30911036 PMCID: PMC6433925 DOI: 10.1038/s41419-019-1517-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/30/2019] [Accepted: 03/01/2019] [Indexed: 01/05/2023]
Abstract
During cortical development, neuronal migration is one of the most important steps for normal cortical formation and function, and defects in this process cause many brain diseases. However, the molecular mechanisms underlying this process remain largely unknown. In this study, we found that miR-129-5p and miR-129-3p were expressed in both neural progenitor cells and cortical neurons in the developing murine cortex. Moreover, abnormal miR-129 expression could block radial migration of both the deeper layer and upper layer neurons, and impair the multipolar to bipolar transition. However, antagomir-mediated inhibition resulted in overmigration of neurons. In addition, we showed that Fragile X Mental Retardation gene 1 (Fmr1), which is mutated in the autism spectrum disorder fragile X syndrome, is an important regulatory target for miR-129-5p. Furthermore, Fmr1 loss-of-function and gain-of-function experiments showed opposite effects on miR-129 regulation of neuronal migration, and restoring Fmr1 expression could counteract the deleterious effect of miR-129 on neuronal migration. Taken together, our results suggest that miR-129-5p could modulate the expression of fragile X mental retardation 1 protein (FMRP) to ensure normal neuron positioning in the developing cerebral cortex.
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Affiliation(s)
- Chao Wu
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Xiaoling Zhang
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Pan Chen
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Xiangbin Ruan
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Wei Liu
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Yanchao Li
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Changjie Sun
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Lin Hou
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Bin Yin
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Boqin Qiang
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China
| | - Pengcheng Shu
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China.
| | - Xiaozhong Peng
- The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, 100005, Beijing, China.
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, 650118, Kunming, China.
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28
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Nampoothiri SS, Rajanikant GK. miR-9 Upregulation Integrates Post-ischemic Neuronal Survival and Regeneration In Vitro. Cell Mol Neurobiol 2019; 39:223-240. [PMID: 30539420 PMCID: PMC11469860 DOI: 10.1007/s10571-018-0642-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 12/07/2018] [Indexed: 01/02/2023]
Abstract
The irrefutable change in the expression of brain-enriched microRNAs (miRNAs) following ischemic stroke has promoted the development of radical miRNA-based therapeutics encompassing neuroprotection and neuronal restoration. Our previous report on the systems-level prediction of miR-9 in post-stroke-induced neurogenesis served as a premise to experimentally uncover the functional role of miR-9 in post-ischemic neuronal survival and regeneration. The oxygen-glucose deprivation (OGD) in SH-SY5Y cells significantly reduced miR-9 expression, while miR-9 mimic transfection enhanced post-ischemic neuronal cell viability. The next major objective involved the execution of a drug repositioning strategy to augment miR-9 expression via structure-based screening of Food and Drug Administration (FDA)-approved drugs that bind to Histone Deacetylase 4 (HDAC4), a known miR-9 target. Glucosamine emerged as the top hit and its binding potential to HDAC4 was verified by Molecular Dynamics (MD) Simulation, Drug Affinity Responsive Target Stability (DARTS) assay, and MALDI-TOF MS. It was intriguing that the glucosamine treatment 1-h post-OGD was associated with the increased miR-9 level as well as enhanced neuronal viability. miR-9 mimic or post-OGD glucosamine treatment significantly increased the cellular proliferation (BrdU assay), while the neurite outgrowth assay displayed elongated neurites. The enhanced BCL2 and VEGF parallel with the reduced NFκB1, TNF-α, IL-1β, and iNOS mRNA levels in miR-9 mimic or glucosamine-treated cells further substantiated their post-ischemic neuroprotective and regenerative efficacy. Hence, this study unleashes a potential therapeutic approach that integrates neuronal survival and regeneration via small-molecule-based regulation of miR-9 favoring long-term recovery against ischemic stroke.
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Affiliation(s)
- Sreekala S Nampoothiri
- School of Biotechnology, National Institute of Technology Calicut, Calicut, 673601, India
| | - G K Rajanikant
- School of Biotechnology, National Institute of Technology Calicut, Calicut, 673601, India.
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29
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Pan WL, Chopp M, Fan B, Zhang R, Wang X, Hu J, Zhang XM, Zhang ZG, Liu XS. Ablation of the microRNA-17-92 cluster in neural stem cells diminishes adult hippocampal neurogenesis and cognitive function. FASEB J 2019; 33:5257-5267. [PMID: 30668139 DOI: 10.1096/fj.201801019r] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Impairment of adult neurogenesis in the hippocampus causes cognitive deficits; however, the underlying molecular mechanisms have not been fully elucidated. microRNAs (miRNAs) regulate neural stem cell (NSC) function. With the use of a transgenic mouse line with conditional ablation of the miR-17-92 cluster in nestin lineage NSCs, we tested the hypothesis that the miR-17-92 cluster regulates adult neurogenesis and cognitive function in vivo. Compared with wild-type mice, ablation of the miR-17-92 cluster significantly reduced the number of proliferating NSCs and neuroblasts and neuronal differentiation in the dentate gyrus (DG) of the hippocampus and significantly impaired hippocampal-dependent learning and memory, as assayed by social recognition memory, novel object recognition, and Morris water-maze tests. Statistical analysis showed a highly significant correlation between newly generated neuroblasts in the DG and cognition deficits in miR-17-92 knockout (KO) mice. Western blot analysis showed that conditional KO of the miR-17-92 cluster significantly increased and reduced a cytoskeleton-associated protein, Enigma homolog 1 (ENH1), and its downstream transcription factor, inhibitor of differentiation 1 (ID1), respectively, as well as increased phosphatase and tensin homolog gene. These proteins are related to neuronal differentiation. Our study demonstrates that the miR-17-92 cluster in NSCs is critical for cognitive and behavioral function and regulates neurogenesis and that the miR-17-92 cluster may target ENH1/ID1 signaling.-Pan, W. L., Chopp, M., Fan, B., Zhang, R., Wang, X., Hu, J., Zhang, X. M., Zhang, Z. G., Liu, X. S. Ablation of the microRNA-17-92 cluster in neural stem cells diminishes adult hippocampal neurogenesis and cognitive function.
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Affiliation(s)
- Wan Long Pan
- Department of Microbiology and Immunology, Sichuan Key Laboratory of Medical Imaging, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.,Department of Physics, Oakland University, Rochester, Michigan, USA
| | - Baoyan Fan
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA
| | - Ruilan Zhang
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA
| | - Xinli Wang
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA
| | - Jiani Hu
- Department of Radiology, Wayne State University, Detroit, Michigan, USA
| | - Xiao Ming Zhang
- Department of Radiology, Sichuan Key Laboratory of Medical Imaging, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Zheng Gang Zhang
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA
| | - Xian Shuang Liu
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA
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30
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Higuchi Y, Soga T, Parhar IS. Potential Roles of microRNAs in the Regulation of Monoamine Oxidase A in the Brain. Front Mol Neurosci 2018; 11:339. [PMID: 30271325 PMCID: PMC6149293 DOI: 10.3389/fnmol.2018.00339] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 08/28/2018] [Indexed: 12/15/2022] Open
Abstract
Monoamine oxidase A (MAO-A) is an enzyme that regulates the levels of monoamine neurotransmitters, such as serotonin, noradrenaline and dopamine and it has been used as a therapeutic target for depression. However, MAO-A inhibitors, which directly acts on MAO-A protein, have limited use due to their adverse effects. microRNAs (miRNAs) are 18-22 nucleotide long, small non-coding RNAs, which have recently emerged as regulators of protein levels that could potentially be new therapeutic targets for psychiatric disorders. This review article aims to discuss the current status of the treatment for depression with MAO-A inhibitors and the regulatory factors of MAO-A. Further, the review also proposes possible regulatory mechanisms of MAO-A by miRNAs, which leads to better understanding of the pathology of depressive disorders and their potential use as therapeutic agents.
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Affiliation(s)
| | | | - Ishwar S. Parhar
- Brain Research Institute, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia
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31
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Li Y, Liu Y, Fan J, Zhou Q, Song X, Peng Z, Qin Z, Tao T. Validation and bioinformatic analysis of propofol-induced differentially expressed microRNAs in primary cultured neural stem cells. Gene 2018; 664:90-100. [PMID: 29679758 DOI: 10.1016/j.gene.2018.04.046] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 03/26/2018] [Accepted: 04/16/2018] [Indexed: 11/27/2022]
Abstract
Propofol, a widely used intravenous anesthetic, was previously considered as a neuroprotective agent. Recently, however, accumulating evidence suggests that it may cause neurotoxicity, especially in the development of neural stem cells (NSCs). The potential mechanisms contributing to propofol-induced neurotoxicity during neurogenesis, such as those involving microRNAs (miRNAs), are still unknown. In this study, a total of 27 differentially expressed miRNAs were identified in our initial screen and 6 miRNAs were validated by qRT-PCR. Three miRNAs were up-regulated (miR-377-5p, miR-194-3p and miR-143-5p), and three were down-regulated (miR-3583-3p, miR-466b-5p and miR-410-5p). Following gene ontology and KEGG pathway enrichment analysis, Gabbr1, Canca1b and Gabbr2, which are enriched in the GABAergic synapse pathway, were selected as genes potentially playing a role in propofol-induced neurotoxicity. Gabbr1 and Cacna1b, which are targeted by miRNAs that are up-regulated following propofol exposure, showed decreased expression at the mRNA and protein levels. Gabbr2, targeted by miRNAs that were down-regulated following treatment with propofol, was up-regulated at both the levels of mRNA and protein expression. The two clusters of miRNAs that show differential expression following propofol exposure may act in a synergistic manner to regulate several genes simultaneously during the development of NSCs. Our results may contribute to clarify the molecular mechanism and provide potential therapeutic targets for propofol induced neurotoxicity.
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Affiliation(s)
- Yan Li
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Youtan Liu
- Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jun Fan
- Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Key Laboratory of Psychiatric Disorders of Guangdong Province, Guangzhou, China
| | - Quan Zhou
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiuling Song
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiyong Peng
- Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zaisheng Qin
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Tao Tao
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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32
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Xia X, Teotia P, Ahmad I. Lin28a regulates neurogliogenesis in mammalian retina through the Igf signaling. Dev Biol 2018; 440:113-128. [PMID: 29758178 DOI: 10.1016/j.ydbio.2018.05.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 04/23/2018] [Accepted: 05/10/2018] [Indexed: 01/02/2023]
Abstract
In the developing central nervous system (CNS) the majority of neurons are born before the generation of glia. Emerging evidence implicates heterochronic gene, Lin28 in the temporal switch between two distinct lineages. However, the respective contributions of Lin28a and Lin28b in neurogliogenesis remain poorly understood. Here, we have examined the relative involvement of Lin28a and Lin28b in mammalian retina, a simple and accessible CNS model where neurogliogenic decision largely occurs postnatally. Examination of Lin28a/b involvement during late histogenesis by the perturbation of function approaches revealed that while Lin28b did not influence differentiation in general Lin28a facilitated and antagonized the generation of neurons and glia, respectively. Silencing of Lin28a expression in vitro and its conditional deletion in vivo during early histogenesis led to premature generation of glia. The instructive role of Lin28a on neuronal differentiation was revealed by its influence to suppress glial-specific genes and directly differentiate glia along the neuronal lineage. This function of Lin28a is likely mediated through the Igf signaling, as inhibition of the pathway abrogated Lin28a-mediated neurogliogenesis. Thus, our observations suggest that Lin28a is an important intrinsic factor that acts in concert with cell-extrinsic factors like Igfs, coordinating the developmental bias of the progenitors and niche, respectively, for the successive generation of neurons and glia.
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Affiliation(s)
- Xiaohuan Xia
- Department of Ophthalmology and Visual Science, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Pooja Teotia
- Department of Ophthalmology and Visual Science, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Iqbal Ahmad
- Department of Ophthalmology and Visual Science, University of Nebraska Medical Center, Omaha, NE 68198, United States.
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Homan CC, Pederson S, To TH, Tan C, Piltz S, Corbett MA, Wolvetang E, Thomas PQ, Jolly LA, Gecz J. PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 Girls Clustering Epilepsy. Neurobiol Dis 2018; 116:106-119. [PMID: 29763708 DOI: 10.1016/j.nbd.2018.05.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/25/2018] [Accepted: 05/09/2018] [Indexed: 01/12/2023] Open
Abstract
PCDH19-Girls Clustering Epilepsy (PCDH19-GCE) is a childhood epileptic encephalopathy characterised by a spectrum of neurodevelopmental problems. PCDH19-GCE is caused by heterozygous loss-of-function mutations in the X-chromosome gene, Protocadherin 19 (PCDH19) encoding a cell-cell adhesion molecule. Intriguingly, hemizygous males are generally unaffected. As PCDH19 is subjected to random X-inactivation, heterozygous females are comprised of a mosaic of cells expressing either the normal or mutant allele, which is thought to drive pathology. Despite being the second most prevalent monogeneic cause of epilepsy, little is known about the role of PCDH19 in brain development. In this study we show that PCDH19 is highly expressed in human neural stem and progenitor cells (NSPCs) and investigate its function in vitro in these cells of both mouse and human origin. Transcriptomic analysis of mouse NSPCs lacking Pcdh19 revealed changes to genes involved in regulation of neuronal differentiation, and we subsequently show that loss of Pcdh19 causes increased NSPC neurogenesis. We reprogramed human fibroblast cells harbouring a pathogenic PCDH19 mutation into human induced pluripotent stem cells (hiPSC) and employed neural differentiation of these to extend our studies into human NSPCs. As in mouse, loss of PCDH19 function caused increased neurogenesis, and furthermore, we show this is associated with a loss of human NSPC polarity. Overall our data suggests a conserved role for PCDH19 in regulating mammalian cortical neurogenesis and has implications for the pathogenesis of PCDH19-GCE. We propose that the difference in timing or "heterochrony" of neuronal cell production originating from PCDH19 wildtype and mutant NSPCs within the same individual may lead to downstream asynchronies and abnormalities in neuronal network formation, which in-part predispose the individual to network dysfunction and epileptic activity.
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Affiliation(s)
- Claire C Homan
- School of Medicine, The University of Adelaide, Adelaide 5005, Australia; Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia; School of Biological Sciences, The University of Adelaide, Adelaide 5005, Australia
| | - Stephen Pederson
- Bioinformatics Hub, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, Australia
| | - Thu-Hien To
- Bioinformatics Hub, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, Australia
| | - Chuan Tan
- School of Medicine, The University of Adelaide, Adelaide 5005, Australia; Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia
| | - Sandra Piltz
- Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia; School of Biological Sciences, The University of Adelaide, Adelaide 5005, Australia; South Australian Health and Medical Research Institute, Adelaide 5000, Australia
| | - Mark A Corbett
- School of Medicine, The University of Adelaide, Adelaide 5005, Australia; Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia; School of Biological Sciences, The University of Adelaide, Adelaide 5005, Australia
| | - Ernst Wolvetang
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Queensland 4072, Australia
| | - Paul Q Thomas
- Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia; School of Biological Sciences, The University of Adelaide, Adelaide 5005, Australia; South Australian Health and Medical Research Institute, Adelaide 5000, Australia
| | - Lachlan A Jolly
- School of Medicine, The University of Adelaide, Adelaide 5005, Australia; Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia.
| | - Jozef Gecz
- School of Medicine, The University of Adelaide, Adelaide 5005, Australia; Robinson Research Institute, The University of Adelaide, Adelaide 5006, Australia; School of Biological Sciences, The University of Adelaide, Adelaide 5005, Australia; South Australian Health and Medical Research Institute, Adelaide 5000, Australia.
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Bielefeld P, Mooney C, Henshall DC, Fitzsimons CP. miRNA-Mediated Regulation of Adult Hippocampal Neurogenesis; Implications for Epilepsy. Brain Plast 2017; 3:43-59. [PMID: 29765859 PMCID: PMC5928558 DOI: 10.3233/bpl-160036] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hippocampal neural stem/progenitor cells (NSPCs) proliferate and differentiate to generate new neurons across the life span of most mammals, including humans. This process takes place within a characteristic local microenvironment where NSPCs interact with a variety of other cell types and encounter systemic regulatory factors. Within this microenvironment, cell intrinsic gene expression programs are modulated by cell extrinsic signals through complex interactions, in many cases involving short non-coding RNA molecules, such as miRNAs. Here we review the regulation of gene expression in NSPCs by miRNAs and its possible implications for epilepsy, which has been linked to alterations in adult hippocampal neurogenesis.
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Affiliation(s)
- Pascal Bielefeld
- Neuroscience Program, Swammerdam Institute for Life Sciences, Faculty of Sciences, University of Amsterdam, The Netherlands
| | - Catherine Mooney
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - David C. Henshall
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Carlos P. Fitzsimons
- Neuroscience Program, Swammerdam Institute for Life Sciences, Faculty of Sciences, University of Amsterdam, The Netherlands
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Encinas JM, Fitzsimons CP. Gene regulation in adult neural stem cells. Current challenges and possible applications. Adv Drug Deliv Rev 2017; 120:118-132. [PMID: 28751200 DOI: 10.1016/j.addr.2017.07.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 07/17/2017] [Accepted: 07/19/2017] [Indexed: 12/13/2022]
Abstract
Adult neural stem and progenitor cells (NSPCs) offer a unique opportunity for neural regeneration and niche modification in physiopathological conditions, harnessing the capability to modify from neuronal circuits to glial scar. Findings exposing the vast plasticity and potential of NSPCs have accumulated over the past years and we currently know that adult NSPCs can naturally give rise not only to neurons but also to astrocytes and reactive astrocytes, and eventually to oligodendrocytes through genetic manipulation. We can consider NSPCs as endogenous flexible tools to fight against neurodegenerative and neurological disorders and aging. In addition, NSPCs can be considered as active agents contributing to chronic brain alterations and as relevant cell populations to be preserved, so that their main function, neurogenesis, is not lost in damage or disease. Altogether we believe that learning to manipulate NSPC is essential to prevent, ameliorate or restore some of the cognitive deficits associated with brain disease and injury, and therefore should be considered as target for future therapeutic strategies. The first step to accomplish this goal is to target them specifically, by unveiling and understanding their unique markers and signaling pathways.
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Affiliation(s)
- Juan Manuel Encinas
- Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, 205, 48170 Zamudio, Spain; Ikerbasque, The Basque Science Foundation, María Díaz de Haro 3, 6(th) Floor, 48013 Bilbao, Spain; University of the Basque Country (UPV/EHU), Barrio Sarriena s/n, 48940 Leioa, Spain.
| | - Carlos P Fitzsimons
- Neuroscience Program, Swammerdam Institute for Life Sciences, Faculty of Sciences, University of Amsterdam, SciencePark 904, 1098XH Amsterdam, The Netherlands.
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36
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The human BDNF gene: peripheral gene expression and protein levels as biomarkers for psychiatric disorders. Transl Psychiatry 2016; 6:e958. [PMID: 27874848 PMCID: PMC5314126 DOI: 10.1038/tp.2016.214] [Citation(s) in RCA: 157] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 08/09/2016] [Accepted: 09/12/2016] [Indexed: 12/17/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. The human BDNF gene consists of 11 exons, and distinct BDNF transcripts are produced through the use of alternative promoters and splicing events. The majority of the BDNF transcripts can be detected not only in the brain but also in the blood cells, although no study has yet investigated the differential expression of BDNF transcripts at the peripheral level. This review provides a description of the human BDNF gene structure as well as a summary of clinical and preclinical evidence supporting the role of BDNF in the pathogenesis of psychiatric disorders. We will discuss several mechanisms as possibly underlying BDNF modulation, including epigenetic mechanisms. We will also discuss the potential use of peripheral BDNF as a biomarker for psychiatric disorders, focusing on the factors that can influence BDNF gene expression and protein levels. Within this context, we have also characterized, for we believe the first time, the expression of BDNF transcripts in the blood, with the aim to provide novel insights into the molecular mechanisms and signaling that may regulate peripheral BDNF gene expression levels.
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37
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Fan J, Zhou Q, Qin Z, Tao T. Effect of propofol on microRNA expression in rat primary embryonic neural stem cells. BMC Anesthesiol 2016; 16:95. [PMID: 27737635 PMCID: PMC5064799 DOI: 10.1186/s12871-016-0259-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 09/29/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Propofol is a widely used intravenous anesthetic that is well-known for its protective effect in various human and animal disease models. However, the effects of propofol on neurogenesis, especially on the development of neural stem cells (NSCs), remains unknown. Related microRNAs may act as important regulators in this process. METHODS Published Gene Expression Omnibus (GEO) DataSets related to propofol were selected and re-analyzed to screen neural development-related genes and predict microRNA (miRNA) expression using bioinformatic methods. Screening of the genes and miRNAs was then validated by qRT-PCR analysis of propofol-treated primary embryonic NSCs. RESULTS Four differentially expressed mRNAs were identified in the screen and 19 miRNAs were predicted based on a published GEO DataSet. Two of four mRNAs and four of 19 predicted miRNAs were validated by qRT-PCR analysis of propofol-treated NSCs. Rno-miR-19a (Rno, Rattus Norvegicus) and rno-miR-137, and their target gene EGR2, as well as rno-miR-19b-2 and rno-miR-214 and their target gene ARC were found to be closely related to neural developmental processes, including proliferation, differentiation, and maturation of NSCs. CONCLUSION Propofol influences miRNA expression; however, further studies are required to elucidate the mechanism underlying the effects of propofol on the four miRNAs and their target genes identified in this study. In particular, the influence of propofol on the entire development process of NSCs remains to be clarified.
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Affiliation(s)
- Jun Fan
- Department of Anesthesiology, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong China
| | - Quan Zhou
- Department of Anesthesiology, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong China
| | - Zaisheng Qin
- Department of Anesthesiology, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong China
| | - Tao Tao
- Department of Anesthesiology, Nan Fang Hospital, Southern Medical University, Guangzhou, Guangdong China
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38
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Tsan YC, Morell MH, O'Shea KS. miR-410 controls adult SVZ neurogenesis by targeting neurogenic genes. Stem Cell Res 2016; 17:238-247. [PMID: 27591480 DOI: 10.1016/j.scr.2016.07.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 06/14/2016] [Accepted: 07/11/2016] [Indexed: 11/16/2022] Open
Abstract
Over-expression of the early neural inducer, Noggin, in nestin positive subventricular zone (SVZ), neural stem cells (NSC) promotes proliferation and neuronal differentiation of neural progenitors and inhibits the expression of a CNS-enriched microRNA-410 (miR-410) (Morell et al., 2015). When expressed in neurospheres derived from the adult SVZ, miR-410 inhibits neuronal and oligodendrocyte differentiation, and promotes astrocyte differentiation. miR-410 also reverses the increase in neuronal differentiation and decreased astroglial differentiation caused by Noggin over-expression. Conversely, inhibition of miR-410 activity promotes neuronal and decreases astroglial differentiation of NSC. Using computer prediction algorithms and luciferase reporter assays we identified multiple neurogenic genes including Elavl4 as downstream targets of miR-410 via the canonical miRNA-3'UTR interaction. Over-expression of Elavl4 transcripts without the endogenous 3'UTR rescued the decrease in neuronal differentiation caused by miR-410 overexpression. Interestingly, we also observed that miR-410 affected neurite morphology; over-expression of miR-410 resulted in the formation of short, unbranched neurites. We conclude that miR-410 expression provides a new link between BMP signaling and the crucial lineage choice of adult neural stem cells via its ability to bind and control the expression of neurogenic gene transcripts.
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Affiliation(s)
- Yao-Chang Tsan
- Department of Cell and Developmental Biology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, United States
| | - Maria H Morell
- Department of Cell and Developmental Biology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, United States
| | - K Sue O'Shea
- Department of Cell and Developmental Biology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, United States.
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39
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Cui Y, Han J, Xiao Z, Chen T, Wang B, Chen B, Liu S, Han S, Fang Y, Wei J, Wang X, Ma X, Dai J. The miR-20-Rest-Wnt signaling axis regulates neural progenitor cell differentiation. Sci Rep 2016; 6:23300. [PMID: 26996236 PMCID: PMC4800422 DOI: 10.1038/srep23300] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 03/03/2016] [Indexed: 11/09/2022] Open
Abstract
Increasing evidence suggests that three dimensional (3-D) cell cultures are an improvement over traditional two dimensional (2-D) cell cultures. Current researches have extensively focused on the study of utilizing biomaterial-based 3-D culture systems to study and direct stem-cell fate both in vitro and in vivo. Here in our study, we screened the differential expression patterns of miRNAs between 2-D cultured and 3-D cultured NPCs using microarray analysis. Among these differentially expressed miRNAs, miR-20 was found to increase during differentiation of NPCs. Specifically, the facilitative effect on neural differentiation of miR-20 is mediated, at least in part by directly target the Rest gene, which is essential for preventing neural differentiation and maintaining NPCs self-renewal. Furthermore, the expression of miR-20 was decreased when the WNT pathway was inhibited by knock down of β-catenin or by exogenous Dkk protein, whereas it increased when the WNT pathway was activated by exogenous Wnt3a protein. Overall, miR-20, Rest and Wnt signaling are suggested to be involved in a regulatory circuit that can modulate the neural differention of NPCs. This novel regulatory circuit provides additional insight into how microRNAs interact with signaling molecules during neural differentiation of NPCs, allowing for fine-tuning of intricate cellular processes.
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Affiliation(s)
- Yi Cui
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing 100081, China.,State key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100190, China
| | - Jin Han
- State key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100190, China
| | - Zhifeng Xiao
- State key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100190, China
| | - Tong Chen
- University of Chinese Academy of Sciences, Beijing 100049, China.,The State Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Bin Wang
- State key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100190, China
| | - Bing Chen
- State key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100190, China
| | - Sumei Liu
- State key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100190, China
| | - Sufang Han
- State key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100190, China
| | - Yongxiang Fang
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Public Health of Ministry of Agriculture, Lanzhou Veterinary Research Institute, CAAS, Lanzhou 730046, China
| | - Jianshu Wei
- State key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100190, China
| | - Xiujie Wang
- The State Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Xu Ma
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing 100081, China
| | - Jianwu Dai
- State key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100190, China
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40
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Jönsson ME, Nelander Wahlestedt J, Åkerblom M, Kirkeby A, Malmevik J, Brattaas PL, Jakobsson J, Parmar M. Comprehensive analysis of microRNA expression in regionalized human neural progenitor cells reveals microRNA-10 as a caudalizing factor. Development 2016; 142:3166-77. [PMID: 26395143 PMCID: PMC4582174 DOI: 10.1242/dev.122747] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
MicroRNAs (miRNAs) have been implicated in regulating multiple processes during brain development in various species. However, the function of miRNAs in human brain development remains largely unexplored. Here, we provide a comprehensive analysis of miRNA expression of regionalized neural progenitor cells derived from human embryonic stem cells and human foetal brain. We found miR-92b-3p and miR-130b-5p to be specifically associated with neural progenitors and several miRNAs that display both age-specific and region-specific expression patterns. Among these miRNAs, we identified miR-10 to be specifically expressed in the human hindbrain and spinal cord, while being absent from rostral regions. We found that miR-10 regulates a large number of genes enriched for functions including transcription, actin cytoskeleton and ephrin receptor signalling. When overexpressed, miR-10 influences caudalization of human neural progenitor cells. Together, these data confirm a role for miRNAs in establishing different human neural progenitor populations. This dataset also provides a comprehensive resource for future studies investigating the functional role of different miRNAs in human brain development. Summary: The profiling of neural progenitors derived from human ESCs and foetal brain shows that miRNAs display region-specific expression patterns, suggesting that they contribute to establishing regional identity.
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Affiliation(s)
- Marie E Jönsson
- Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden
| | - Jenny Nelander Wahlestedt
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden
| | - Malin Åkerblom
- Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden
| | - Agnete Kirkeby
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden
| | - Josephine Malmevik
- Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden
| | - Per Ludvik Brattaas
- Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden
| | - Johan Jakobsson
- Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden
| | - Malin Parmar
- Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden
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41
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Santos MCT, Tegge AN, Correa BR, Mahesula S, Kohnke LQ, Qiao M, Ferreira MAR, Kokovay E, Penalva LOF. miR-124, -128, and -137 Orchestrate Neural Differentiation by Acting on Overlapping Gene Sets Containing a Highly Connected Transcription Factor Network. Stem Cells 2015; 34:220-32. [PMID: 26369286 DOI: 10.1002/stem.2204] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 08/14/2015] [Indexed: 12/19/2022]
Abstract
The ventricular-subventricular zone harbors neural stem cells (NSCs) that can differentiate into neurons, astrocytes, and oligodendrocytes. This process requires loss of stem cell properties and gain of characteristics associated with differentiated cells. miRNAs function as important drivers of this transition; miR-124, -128, and -137 are among the most relevant ones and have been shown to share commonalities and act as proneurogenic regulators. We conducted biological and genomic analyses to dissect their target repertoire during neurogenesis and tested the hypothesis that they act cooperatively to promote differentiation. To map their target genes, we transfected NSCs with antagomiRs and analyzed differences in their mRNA profile throughout differentiation with respect to controls. This strategy led to the identification of 910 targets for miR-124, 216 for miR-128, and 652 for miR-137. The target sets show extensive overlap. Inspection by gene ontology and network analysis indicated that transcription factors are a major component of these miRNAs target sets. Moreover, several of these transcription factors form a highly interconnected network. Sp1 was determined to be the main node of this network and was further investigated. Our data suggest that miR-124, -128, and -137 act synergistically to regulate Sp1 expression. Sp1 levels are dramatically reduced as cells differentiate and silencing of its expression reduced neuronal production and affected NSC viability and proliferation. In summary, our results show that miRNAs can act cooperatively and synergistically to regulate complex biological processes like neurogenesis and that transcription factors are heavily targeted to branch out their regulatory effect.
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Affiliation(s)
- Márcia C T Santos
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Allison N Tegge
- Department of Computer Science, Virginia Tech, Blacksburg, Virginia, USA.,Department of Statistics, Virginia Tech, Blacksburg, Virginia, USA
| | - Bruna R Correa
- Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil
| | - Swetha Mahesula
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Luana Q Kohnke
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Mei Qiao
- Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | | | - Erzsebet Kokovay
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Luiz O F Penalva
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
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Huang Y, Liu X, Wang Y. MicroRNA-378 regulates neural stem cell proliferation and differentiation in vitro by modulating Tailless expression. Biochem Biophys Res Commun 2015; 466:214-20. [PMID: 26361139 DOI: 10.1016/j.bbrc.2015.09.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 09/03/2015] [Indexed: 12/21/2022]
Abstract
Previous studies have suggested that microRNAs (miRNAs) play an important role in regulating neural stem cell (NSC) proliferation and differentiation. However, the precise role of miRNAs in NSC remains largely unexplored. In this study, we showed that miR-378 can target Tailless (TLX), a critical regulator of NSC, to regulate NSC proliferation and differentiation. By bioinformatic algorithms, miR-378 was found to have a predicted target site in the 3'-untranslated region of TLX, which was verified by a dual-luciferase reporter assay. The expression of miR-378 was increased during NSC differentiation and inversely correlated with TLX expression. qPCR and Western blot analysis also showed that miR-378 negatively regulated TLX mRNA and protein expression in neural stem cells (NSCs). Intriguingly, overexpression of miR-378 increased NSC differentiation and reduced NSC proliferation, whereas suppression of miR-378 led to decreased NSC differentiation and increased NSC proliferation. Moreover, the downstream targets of TLX, including p21, PTEN and Wnt/β-catenin were also found to be regulated by miR-378. Additionally, overexpression of TLX rescued the NSC proliferation deficiency induced by miR-378 overexpression and abolished miR-378-promoted NSC differentiation. Taken together, our data suggest that miR-378 is a novel miRNA that regulates NSC proliferation and differentiation via targeting TLX. Therefore, manipulating miR-378 in NSCs could be a novel strategy to develop novel interventions for the treatment of relevant neurological disorders.
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Affiliation(s)
- Yanxia Huang
- Department of Psychology and Psychiatry, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China; Department of Rehabilitation, Xi'an Children's Hospital, Xi'an 710003, China
| | - Xiaoguai Liu
- The 3rd Department of Infectious Diseases, Xi'an Children's Hospital, Xi'an 710003, China
| | - Yaping Wang
- Department of Psychology and Psychiatry, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
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Dwivedi Y. Emerging role of microRNAs in major depressive disorder: diagnosis and therapeutic implications. DIALOGUES IN CLINICAL NEUROSCIENCE 2014. [PMID: 24733970 PMCID: PMC3984890 DOI: 10.31887/dcns.2014.16.1/ydwivedi] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Major depressive disorder (MDD) is a major public health concern. Despite tremendous advances, the pathogenic mechanisms associated with MDD are still unclear. Moreover, a significant number of MDD subjects do not respond to the currently available medication. MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by modulating translation, messenger RNA (mRNA) degradation, or stability of mRNA targets. The role of miRNAs in disease pathophysiology is emerging rapidly. Recent studies demonstrating the involvement of miRNAs in several aspects of neural plasticity, neurogenesis, and stress response, and more direct studies in human postmortem brain provide strong evidence that miRNAs can not only play a critical role in MDD pathogenesis, but can also open up new avenues for the development of therapeutic targets. Circulating miRNAs are now being considered as possible biomarkers in disease pathogenesis and in monitoring therapeutic responses because of the presence and/or release of miRNAs in blood cells as well as in other peripheral tissues. In this review, these aspects are discussed in a comprehensive and critical manner.
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Affiliation(s)
- Yogesh Dwivedi
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Alabama, USA
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Ni N, Zhang D, Xie Q, Chen J, Wang Z, Deng Y, Wen X, Zhu M, Ji J, Fan X, Luo M, Gu P. Effects of let-7b and TLX on the proliferation and differentiation of retinal progenitor cells in vitro. Sci Rep 2014; 4:6671. [PMID: 25327364 PMCID: PMC4202307 DOI: 10.1038/srep06671] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 08/21/2014] [Indexed: 02/03/2023] Open
Abstract
MicroRNAs manifest significant functions in brain neural stem cell (NSC) self-renewal and differentiation through the post-transcriptional regulation of neurogenesis genes. Let-7b is expressed in the mammalian brain and regulates NSC proliferation and differentiation by targeting the nuclear receptor TLX, which is an essential regulator of NSC self-renewal. Whether let-7b and TLX act as important regulators in retinal progenitor cell (RPC) proliferation and differentiation remains unknown. Here, our data show that let-7b and TLX play important roles in controlling RPC fate determination in vitro. Let-7b suppresses TLX expression to negatively regulate RPC proliferation and accelerate the neuronal and glial differentiation of RPCs. The overexpression of let-7b downregulates TLX levels in RPCs, leading to reduced RPC proliferation and increased neuronal and glial differentiation, whereas antisense knockdown of let-7b produces robust TLX expression,enhanced RPC proliferation and decreased differentiation. Moreover, the inhibition of endogenous TLX by small interfering RNA suppresses RPC proliferation and promotes RPC differentiation. Furthermore, overexpression of TLX rescues let-7b-induced proliferation deficiency and weakens the RPC differentiation enhancement caused by let-7b alone. These results suggest that let-7b, by forming a negative feedback loop with TLX, provides a novel model to regulate the proliferation and differentiation of retinal progenitors in vitro.
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Affiliation(s)
- Ni Ni
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Dandan Zhang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Qing Xie
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Junzhao Chen
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Zi Wang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Yuan Deng
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Xuyang Wen
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Mengyu Zhu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Jing Ji
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Xianqun Fan
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Min Luo
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
| | - Ping Gu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200011, China
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Tuoc TC, Pavlakis E, Tylkowski MA, Stoykova A. Control of cerebral size and thickness. Cell Mol Life Sci 2014; 71:3199-218. [PMID: 24614969 PMCID: PMC11113230 DOI: 10.1007/s00018-014-1590-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 02/10/2014] [Accepted: 02/13/2014] [Indexed: 11/24/2022]
Abstract
The mammalian neocortex is a sheet of cells covering the cerebrum that provides the structural basis for the perception of sensory inputs, motor output responses, cognitive function, and mental capacity of primates. Recent discoveries promote the concept that increased cortical surface size and thickness in phylogenetically advanced species is a result of an increased generation of neurons, a process that underlies higher cognitive and intellectual performance in higher primates and humans. Here, we review some of the advances in the field, focusing on the diversity of neocortical progenitors in different species and the cellular mechanisms of neurogenesis. We discuss recent views on intrinsic and extrinsic molecular determinants, including the role of epigenetic chromatin modifiers and microRNA, in the control of neuronal output in developing cortex and in the establishment of normal cortical architecture.
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Affiliation(s)
- Tran Cong Tuoc
- Institute of Neuroanatomy, Universitätsmedizin Göttingen, Kreuzbergring 40, 37075, Göttingen, Germany,
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46
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Sun E, Shi Y. MicroRNAs: Small molecules with big roles in neurodevelopment and diseases. Exp Neurol 2014; 268:46-53. [PMID: 25128264 DOI: 10.1016/j.expneurol.2014.08.005] [Citation(s) in RCA: 134] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 07/29/2014] [Accepted: 08/05/2014] [Indexed: 01/13/2023]
Abstract
MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules that play important roles in the development and functions of the brain. Extensive studies have revealed critical roles for miRNAs in brain development and function. Dysregulation or altered expression of miRNAs is associated with abnormal brain development and pathogenesis of neurodevelopmental diseases. This review serves to highlight the versatile roles of these small RNA molecules in normal brain development and their association with neurodevelopmental disorders, in particular, two closely related neuropsychiatric disorders of neurodevelopmental origin, schizophrenia and bipolar disorder.
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Affiliation(s)
- Emily Sun
- Department of Neurosciences, Cancer Center, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Yanhong Shi
- Department of Neurosciences, Cancer Center, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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Abstract
Epigenetic modulations orchestrate with extracellular environmental cues to determine the spatial and temporal expression of key regulators in neural stem/progenitor cells to control their proliferation, fate specification, and differentiation. Here, Yao and Jin review the latest in our knowledge of epigenetic regulation in neurogenesis and offer a perspective for future studies. During embryonic and adult neurogenesis, neuronal stem cells follow a highly conserved path of differentiation to give rise to functional neurons at various developmental stages. Epigenetic regulation—including DNA modifications, histone modifications, and noncoding regulatory RNAs, such as microRNA (miRNA) and long noncoding RNA (lncRNA)—plays a pivotal role in embryonic and adult neurogenesis. Here we review the latest in our understanding of the epigenetic regulation in neurogenesis, with a particular focus on newly identified cytosine modifications and their dynamics, along with our perspective for future studies.
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Affiliation(s)
- Bing Yao
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA
| | - Peng Jin
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA
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Islam MM, Zhang CL. TLX: A master regulator for neural stem cell maintenance and neurogenesis. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2014; 1849:210-6. [PMID: 24930777 DOI: 10.1016/j.bbagrm.2014.06.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 04/22/2014] [Accepted: 06/05/2014] [Indexed: 10/25/2022]
Abstract
The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests that the misregulation of TLX might play a role in the onset and progression of human neurological disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
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Affiliation(s)
- Mohammed M Islam
- Department of Molecular Biology, 6000 Harry Hines Blvd., Dallas, TX 75390, USA
| | - Chun-Li Zhang
- Department of Molecular Biology, 6000 Harry Hines Blvd., Dallas, TX 75390, USA.
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49
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Volvert ML, Prévot PP, Close P, Laguesse S, Pirotte S, Hemphill J, Rogister F, Kruzy N, Sacheli R, Moonen G, Deiters A, Merkenschlager M, Chariot A, Malgrange B, Godin JD, Nguyen L. MicroRNA targeting of CoREST controls polarization of migrating cortical neurons. Cell Rep 2014; 7:1168-83. [PMID: 24794437 DOI: 10.1016/j.celrep.2014.03.075] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 10/08/2013] [Accepted: 03/31/2014] [Indexed: 12/13/2022] Open
Abstract
The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. The molecular basis of these changes remains elusive, and the present work describes how microRNAs (miRNAs) control neuronal polarization during radial migration. We show that miR-22 and miR-124 are expressed in the cortical wall where they target components of the CoREST/REST transcriptional repressor complex, thereby regulating doublecortin transcription in migrating neurons. This molecular pathway underlies radial migration by promoting dynamic multipolar-bipolar cell conversion at early phases of migration, and later stabilization of cell polarity to support locomotion on radial glia fibers. Thus, our work emphasizes key roles of some miRNAs that control radial migration during cerebral corticogenesis.
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Affiliation(s)
- Marie-Laure Volvert
- GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - Pierre-Paul Prévot
- GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - Pierre Close
- GIGA-Signal Transduction, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - Sophie Laguesse
- GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - Sophie Pirotte
- GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - James Hemphill
- Department of Chemistry, North Carolina State University, Raleigh, NC 27695, USA; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Florence Rogister
- GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - Nathalie Kruzy
- GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - Rosalie Sacheli
- GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - Gustave Moonen
- GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - Alexander Deiters
- Department of Chemistry, North Carolina State University, Raleigh, NC 27695, USA; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Matthias Merkenschlager
- Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, UK
| | - Alain Chariot
- GIGA-Signal Transduction, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Walloon Excellence in Lifesciences and Biotechnology (WELBIO), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - Brigitte Malgrange
- GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - Juliette D Godin
- GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium
| | - Laurent Nguyen
- GIGA-Neurosciences, University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium; Walloon Excellence in Lifesciences and Biotechnology (WELBIO), University of Liège, C.H.U. Sart Tilman, Liège 4000, Belgium.
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50
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Sangiao-Alvarellos S, Pena-Bello L, Manfredi-Lozano M, Tena-Sempere M, Cordido F. Perturbation of hypothalamic microRNA expression patterns in male rats after metabolic distress: impact of obesity and conditions of negative energy balance. Endocrinology 2014; 155:1838-50. [PMID: 24517225 DOI: 10.1210/en.2013-1770] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The hypothalamus plays a crucial role in body weight homeostasis through an intricate network of neuronal circuits that are under the precise regulation of peripheral hormones and central transmitters. Although deregulated function of such circuits might be a major contributing factor in obesity, the molecular mechanisms responsible for the hypothalamic control of energy balance remain partially unknown. MicroRNAs (miRNAs) have been recognized as key regulators of different biological processes, including insulin sensitivity and glucose metabolism. However, the roles of miRNA pathways in the control of metabolism have been mostly addressed in peripheral tissues, whereas the potential deregulation of miRNA expression in the hypothalamus in conditions of metabolic distress remains as yet unexplored. In this work, we used high-throughput screening to define to what extent the hypothalamic profiles of miRNA expression are perturbed in two extreme conditions of nutritional stress in male rats, namely chronic caloric restriction and high-fat diet-induced obesity. Our analyses allowed the identification of sets of miRNAs, including let-7a, mir-9*, mir-30e, mir-132, mir-145, mir-200a, and mir-218, whose expression patterns in the hypothalamus were jointly altered by caloric restriction and/or a high-fat diet. The predicted targets of these miRNAs include several elements of key inflammatory and metabolic pathways, including insulin and leptin. Our study is the first to disclose the impact of nutritional challenges on the hypothalamic miRNA expression profiles. These data will help to characterize the molecular miRNA signature of the hypothalamus in extreme metabolic conditions and pave the way for targeted mechanistic analyses of the involvement of deregulated central miRNAs pathways in the pathogenesis of obesity and related disorders.
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Affiliation(s)
- Susana Sangiao-Alvarellos
- Department of Medicine (S.S.-A., L.P.-B., F.C.), School of Health Science, University of A Coruña, Campus de Oza, 15006 A Coruña, Spain; Instituto de Investigación Biomédica de A Coruña (S.S.-A., L.P.-B., F.C.), Xubias de Arriba, 84, 15006 A Coruña, Spain; Division of Endocrinology (L.P.-B., F.C.), Complexo Hospitalario Universitario de A Coruña (CHUAC), 15006 A Coruña, Spain; and Department of Cell Biology (M.M.-L., M.T.-S.), Physiology and Immunology, University of Córdoba, Centro de Investigación Biomédica en Red, Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, and Instituto Maimónides de Investigación Biomédica/Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
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