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Gu Y, Li Y, Zhang C, Liu Y, Shi H, Tian X, Du J, Zhang H, Cao S, Gao L, Zhang Y, Zhao G. BCL6 Alleviates Hepatic Ischemia/Reperfusion Injury Via Recruiting SIRT1 to Repress the NF-κB/NLRP3 Pathway. Transplantation 2025; 109:e297-e310. [PMID: 39800885 PMCID: PMC12091221 DOI: 10.1097/tp.0000000000005305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 09/24/2024] [Accepted: 09/26/2024] [Indexed: 03/19/2025]
Abstract
BACKGROUND Hepatic ischemia/reperfusion (I/R) injury (HIRI) is an intrinsic phenomenon observed in the process of various liver surgeries. Unfortunately, there are currently few options available to prevent HIRI. Accordingly, we aim to explore the role and key downstream effects of B-cell lymphoma 6 (BCL6) in hepatic I/R (HIR). METHODS BCL6 expression levels were measured in I/R liver tissue and primary hepatocytes stimulated by hypoxia/reoxygenation (H/R). Moreover, we ascertained the BCL6 effect on HIR in vivo using liver-specific BCL6 knockout mice and adenovirus-BCL6-infected mice. RNA-sequencing, luciferase, chromatin immunoprecipitation, and interactome analysis were combined to identify the direct target and corresponding molecular events contributing to BCL6 function. DNA pull-down was applied to identify upstream of BCL6 in the H/R challenge. RESULTS HIR represses BCL6 expression in vivo and in vitro. Hepatic BCL6 overexpression attenuates inflammation and apoptosis after I/R injury, whereas BCL6 deficiency aggravates I/R-induced liver injury. RNA-sequencing showed that BCL6 modulated nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 inflammasome signaling in HIRI. Mechanistically, BCL6 deacetylated nuclear factor kappa-B p65 lysine 310 by recruiting sirtuin 1 (SIRT1), thereby inhibiting the nuclear factor kappa-B/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 pathway. Moreover, overexpression of SIRT1 blocked the detrimental effects of BCL6 depletion. Moreover, EX 527, a SIRT1 inhibitor, vanished protection from BCL6 overexpression. Furthermore, transcription factor 7 was found to mediate the transcription regulation of BCL6 on H/R challenge. CONCLUSIONS Our results provide the first evidence supporting BCL6 as an important protective agent of HIR. This suggests a potential therapeutic approach for HIR.
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Affiliation(s)
- Yulei Gu
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, China
| | - Yue Li
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Chao Zhang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Liu
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Henan, China
| | - Huiting Shi
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Xiaoxu Tian
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Jiaqi Du
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Hao Zhang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shengli Cao
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, Henan, China
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lu Gao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Yanzhou Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Guojun Zhao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
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Yao TF, Wang ZY, Sun L, Yu SX, Yu HD, Yang ZZ, Li WZ, Niu L, Sun D, Shi YH, Li JQ, Liu WQ, Liu XZ, Zuo ZF. DNMT3b-mediated CpA methylation facilitates REST binding and gene silencing and exacerbates hippocampal demyelination in diabetic mice. J Biol Chem 2025; 301:108137. [PMID: 39730060 PMCID: PMC11910331 DOI: 10.1016/j.jbc.2024.108137] [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: 09/03/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 12/29/2024] Open
Abstract
The remyelination process within the diabetes mellitus (DM) brain is inhibited, and dynamic interactions between DNA methylation and transcription factors are critical for this process. Repressor element-1 silencing transcription factor (REST) is a major regulator of oligodendrocyte differentiation, and the role of REST on DM remyelination remains to be investigated. Here, we investigated the effects of REST and DNA methylation on DM remyelination and explored the underlying mechanisms. In this study, using a diabetic mouse model, we found that myelin damage preceded neuronal damage and caused cognitive impairment in DM mice. Inhibition of REST by X5050 and DNMT3b by Naomycin A promoted myelin regeneration in the hippocampus and ameliorated cognitive deficits in DM mice. In addition, CpA methylation of the RE-1 locus of the CNTN1 gene was able to increase the binding capacity of REST. We also observed that CNTN1 promotes oligodendrocyte maturation, facilitates the ratio of microglia to pro-regenerative phenotypes as well as enhances the ability of microglia to remove myelin debris. Our findings suggest that REST and DNMT3b expression inhibit CNTN1 expression and exacerbate myelin damage. This mechanism of gene silencing may be associated with DNMT3b-mediated CpA methylation of the REST binding site in the promoter region of the CNTN1 gene. We also identified the role for CNTN1 in promoting oligodendrocyte precursor cell maturation and myelin debris removal during remyelination.
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Affiliation(s)
- Tie-Feng Yao
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Zhi-Yun Wang
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China
| | - Lu Sun
- Department of Pathology, Jinzhou Medical University, Jinzhou, China
| | - Sheng-Xue Yu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Hong-Dan Yu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Zheng-Zhong Yang
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Wan-Ze Li
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Lin Niu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Die Sun
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Ya-Hui Shi
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Jun-Qi Li
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Wen-Qiang Liu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China
| | - Xue-Zheng Liu
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China.
| | - Zhong-Fu Zuo
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China; Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China.
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Sethi P, Mehan S, Khan Z, Maurya PK, Kumar N, Kumar A, Tiwari A, Sharma T, Das Gupta G, Narula AS, Kalfin R. The SIRT-1/Nrf2/HO-1 axis: Guardians of neuronal health in neurological disorders. Behav Brain Res 2025; 476:115280. [PMID: 39368713 DOI: 10.1016/j.bbr.2024.115280] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/10/2024] [Accepted: 09/30/2024] [Indexed: 10/07/2024]
Abstract
SIRT1 (Sirtuin 1) is a NAD+-dependent deacetylase that functions through nucleoplasmic transfer and is present in nearly all mammalian tissues. SIRT1 is believed to deacetylate its protein substrates, resulting in neuroprotective actions, including reduced oxidative stress and inflammation, increased autophagy, increased nerve growth factors, and preserved neuronal integrity in aging or neurological disease. Nrf2 is a transcription factor that regulates the genes responsible for oxidative stress response and substance detoxification. The activation of Nrf2 guards cells against oxidative damage, inflammation, and carcinogenic stimuli. Several neurological abnormalities and inflammatory disorders have been associated with variations in Nrf2 activation caused by either pharmacological or genetic factors. Recent evidence indicates that Nrf2 is at the center of a complex cellular regulatory network, establishing it as a transcription factor with genuine pleiotropy. HO-1 is most likely a component of a defense mechanism in cells under stress, as it provides negative feedback for cell activation and mediator synthesis. This mediator is upregulated by Nrf2, nitric oxide (NO), and other factors in various inflammatory states. HO-1 or its metabolites, such as CO, may mitigate inflammation by modulating signal transduction pathways. Neurological diseases may be effectively treated by modulating the activity of HO-1. Multiple studies have demonstrated that SIRT1 and Nrf2 share an important connection. SIRT1 enhances Nrf2, activates HO-1, protects against oxidative injury, and decreases neuronal death. This has been associated with numerous neurodegenerative and neuropsychiatric disorders. Therefore, activating the SIRT1/Nrf2/HO-1 pathway may help treat various neurological disorders. This review focuses on the current understanding of the SIRT1 and Nrf2/HO-1 neuroprotective processes and the potential therapeutic applications of their target activators in neurodegenerative and neuropsychiatric disorders.
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Affiliation(s)
- Pranshul Sethi
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Sidharth Mehan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India.
| | - Zuber Khan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Pankaj Kumar Maurya
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh 201204, India
| | - Aakash Kumar
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Aarti Tiwari
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Tarun Sharma
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Ghanshyam Das Gupta
- Department of Pharmaceutics, ISF College of Pharmacy (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Acharan S Narula
- Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC 27516, USA
| | - Reni Kalfin
- Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. G. Bonchev St., Block 23, Sofia 1113, Bulgaria; Department of Healthcare, South-West University "NeofitRilski", Ivan Mihailov St. 66, Blagoevgrad 2700, Bulgaria
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Liongue C, Almohaisen FLJ, Ward AC. B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond. Int J Mol Sci 2024; 25:10968. [PMID: 39456751 PMCID: PMC11507070 DOI: 10.3390/ijms252010968] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/09/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
B cell lymphoma 6 (BCL6) is a conserved multi-domain protein that functions principally as a transcriptional repressor. This protein regulates many pivotal aspects of immune cell development and function. BCL6 is critical for germinal center (GC) formation and the development of high-affinity antibodies, with key roles in the generation and function of GC B cells, follicular helper T (Tfh) cells, follicular regulatory T (Tfr) cells, and various immune memory cells. BCL6 also controls macrophage production and function as well as performing a myriad of additional roles outside of the immune system. Many of these regulatory functions are conserved throughout evolution. The BCL6 gene is also important in human oncology, particularly in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), but also extending to many in other cancers, including a unique role in resistance to a variety of therapies, which collectively make BCL6 inhibitors highly sought-after.
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Affiliation(s)
- Clifford Liongue
- School of Medicine, Deakin University, Geelong, VIC 3216, Australia; (C.L.); (F.L.J.A.)
- Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC 3216, Australia
| | - Farooq L. J. Almohaisen
- School of Medicine, Deakin University, Geelong, VIC 3216, Australia; (C.L.); (F.L.J.A.)
- Department of Medical Laboratory Techniques, Southern Technical University, Basra 61001, Iraq
| | - Alister C. Ward
- School of Medicine, Deakin University, Geelong, VIC 3216, Australia; (C.L.); (F.L.J.A.)
- Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC 3216, Australia
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5
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Minto MS, Sotelo-Fonseca JE, Ramesh V, West AE. Genome binding properties of Zic transcription factors underlie their changing functions during neuronal maturation. BMC Biol 2024; 22:189. [PMID: 39218853 PMCID: PMC11367862 DOI: 10.1186/s12915-024-01989-9] [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: 02/06/2024] [Accepted: 08/21/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND The Zic family of transcription factors (TFs) promote both proliferation and maturation of cerebellar granule neurons (CGNs), raising the question of how a single, constitutively expressed TF family can support distinct developmental processes. Here we use an integrative experimental and bioinformatic approach to discover the regulatory relationship between Zic TF binding and changing programs of gene transcription during postnatal CGN differentiation. RESULTS We first established a bioinformatic pipeline to integrate Zic ChIP-seq data from the developing mouse cerebellum with other genomic datasets from the same tissue. In newborn CGNs, Zic TF binding predominates at active enhancers that are co-bound by developmentally regulated TFs including Atoh1, whereas in mature CGNs, Zic TF binding consolidates toward promoters where it co-localizes with activity-regulated TFs. We then performed CUT&RUN-seq in differentiating CGNs to define both the time course of developmental shifts in Zic TF binding and their relationship to gene expression. Mapping Zic TF binding sites to genes using chromatin looping, we identified the set of Zic target genes that have altered expression in RNA-seq from Zic1 or Zic2 knockdown CGNs. CONCLUSIONS Our data show that Zic TFs are required for both induction and repression of distinct, developmentally regulated target genes through a mechanism that is largely independent of changes in Zic TF binding. We suggest that the differential collaboration of Zic TFs with other TF families underlies the shift in their biological functions across CGN development.
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Affiliation(s)
- Melyssa S Minto
- Program in Computational Biology and Bioinformatics, Duke University, Durham, NC, 27710, USA
- Omics, Epidemiology and Analytics Program, RTI International, Research Triangle Park, NC, 27709, USA
| | | | - Vijyendra Ramesh
- Department of Neurobiology, Duke University, Durham, NC, 27710, USA
| | - Anne E West
- Department of Neurobiology, Duke University, Durham, NC, 27710, USA.
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6
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Thor S. Indirect neurogenesis in space and time. Nat Rev Neurosci 2024; 25:519-534. [PMID: 38951687 DOI: 10.1038/s41583-024-00833-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/29/2024] [Indexed: 07/03/2024]
Abstract
During central nervous system (CNS) development, neural progenitor cells (NPCs) generate neurons and glia in two different ways. In direct neurogenesis, daughter cells differentiate directly into neurons or glia, whereas in indirect neurogenesis, neurons or glia are generated after one or more daughter cell divisions. Intriguingly, indirect neurogenesis is not stochastically deployed and plays instructive roles during CNS development: increased generation of cells from specific lineages; increased generation of early or late-born cell types within a lineage; and increased cell diversification. Increased indirect neurogenesis might contribute to the anterior CNS expansion evident throughout the Bilateria and help to modify brain-region size without requiring increased NPC numbers or extended neurogenesis. Increased indirect neurogenesis could be an evolutionary driver of the gyrencephalic (that is, folded) cortex that emerged during mammalian evolution and might even have increased during hominid evolution. Thus, selection of indirect versus direct neurogenesis provides a powerful developmental and evolutionary instrument that drives not only the evolution of CNS complexity but also brain expansion and modulation of brain-region size, and thereby the evolution of increasingly advanced cognitive abilities. This Review describes indirect neurogenesis in several model species and humans, and highlights some of the molecular genetic mechanisms that control this important process.
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Affiliation(s)
- Stefan Thor
- School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia.
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Gomez-Pinilla F, Thapak P. Exercise epigenetics is fueled by cell bioenergetics: Supporting role on brain plasticity and cognition. Free Radic Biol Med 2024; 220:43-55. [PMID: 38677488 PMCID: PMC11144461 DOI: 10.1016/j.freeradbiomed.2024.04.237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/04/2024] [Accepted: 04/24/2024] [Indexed: 04/29/2024]
Abstract
Exercise has the unique aptitude to benefit overall health of body and brain. Evidence indicates that the effects of exercise can be saved in the epigenome for considerable time to elevate the threshold for various diseases. The action of exercise on epigenetic regulation seems central to building an "epigenetic memory" to influence long-term brain function and behavior. As an intrinsic bioenergetic process, exercise engages the function of the mitochondria and redox pathways to impinge upon molecular mechanisms that regulate synaptic plasticity and learning and memory. We discuss how the action of exercise uses mechanisms of bioenergetics to support a "epigenetic memory" with long-term implications for neural and behavioral plasticity. This information is crucial for directing the power of exercise to reduce the burden of neurological and psychiatric disorders.
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Affiliation(s)
- Fernando Gomez-Pinilla
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA; Department of Neurosurgery, UCLA Brain Injury Research Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
| | - Pavan Thapak
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
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Iwata R, Vanderhaeghen P. Metabolic mechanisms of species-specific developmental tempo. Dev Cell 2024; 59:1628-1639. [PMID: 38906137 PMCID: PMC11266843 DOI: 10.1016/j.devcel.2024.05.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 04/27/2024] [Accepted: 05/23/2024] [Indexed: 06/23/2024]
Abstract
Development consists of a highly ordered suite of steps and transitions, like choreography. Although these sequences are often evolutionarily conserved, they can display species variations in duration and speed, thereby modifying final organ size or function. Despite their evolutionary significance, the mechanisms underlying species-specific scaling of developmental tempo have remained unclear. Here, we will review recent findings that implicate global cellular mechanisms, particularly intermediary and protein metabolism, as species-specific modifiers of developmental tempo. In various systems, from somitic cell oscillations to neuronal development, metabolic pathways display species differences. These have been linked to mitochondrial metabolism, which can influence the species-specific speed of developmental transitions. Thus, intermediary metabolic pathways regulate developmental tempo together with other global processes, including proteostasis and chromatin remodeling. By linking metabolism and the evolution of developmental trajectories, these findings provide opportunities to decipher how species-specific cellular timing can influence organism fitness.
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Affiliation(s)
- Ryohei Iwata
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium
| | - Pierre Vanderhaeghen
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium.
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Minto M, Sotelo-Fonseca JE, Ramesh V, West AE. Genome binding properties of Zic transcription factors underlie their changing functions during neuronal maturation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.04.574185. [PMID: 38260638 PMCID: PMC10802290 DOI: 10.1101/2024.01.04.574185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Background The Zic family of transcription factors (TFs) promote both proliferation and maturation of cerebellar granule neurons (CGNs), raising the question of how a single, constitutively expressed TF family can support distinct developmental processes. Here we use an integrative experimental and bioinformatic approach to discover the regulatory relationship between Zic TF binding and changing programs of gene transcription during CGN differentiation. Results We first established a bioinformatic pipeline to integrate Zic ChIP-seq data from the developing mouse cerebellum with other genomic datasets from the same tissue. In newborn CGNs, Zic TF binding predominates at active enhancers that are co-bound by developmentally-regulated TFs including Atoh1, whereas in mature CGNs, Zic TF binding consolidates toward promoters where it co-localizes with activity-regulated TFs. We then performed CUT&RUN-seq in differentiating CGNs to define both the time course of developmental shifts in Zic TF binding and their relationship to gene expression. Mapping Zic TF binding sites to genes using chromatin looping, we identified the set of Zic target genes that have altered expression in RNA-seq from Zic1 or Zic2 knockdown CGNs. Conclusion Our data show that Zic TFs are required for both induction and repression of distinct, developmentally regulated target genes through a mechanism that is largely independent of changes in Zic TF binding. We suggest that the differential collaboration of Zic TFs with other TF families underlies the shift in their biological functions across CGN development.
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Affiliation(s)
- Melyssa Minto
- Duke University, Program in Computational Biology and Bioinformatics, Durham, NC 27710
- GenOmics and Translational Research Center, RTI International, Research Triangle Park, NC 27709
| | | | | | - Anne E. West
- Duke University, Department of Neurobiology, Durham, NC 27710
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10
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Yu J, Chen G, Zhu H, Zhong Y, Yang Z, Jian Z, Xiong X. Metabolic and proteostatic differences in quiescent and active neural stem cells. Neural Regen Res 2024; 19:43-48. [PMID: 37488842 PMCID: PMC10479840 DOI: 10.4103/1673-5374.375306] [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: 09/20/2022] [Revised: 02/16/2023] [Accepted: 04/17/2023] [Indexed: 07/26/2023] Open
Abstract
Adult neural stem cells are neurogenesis progenitor cells that play an important role in neurogenesis. Therefore, neural regeneration may be a promising target for treatment of many neurological illnesses. The regenerative capacity of adult neural stem cells can be characterized by two states: quiescent and active. Quiescent adult neural stem cells are more stable and guarantee the quantity and quality of the adult neural stem cell pool. Active adult neural stem cells are characterized by rapid proliferation and differentiation into neurons which allow for integration into neural circuits. This review focuses on differences between quiescent and active adult neural stem cells in nutrition metabolism and protein homeostasis. Furthermore, we discuss the physiological significance and underlying advantages of these differences. Due to the limited number of adult neural stem cells studies, we referred to studies of embryonic adult neural stem cells or non-mammalian adult neural stem cells to evaluate specific mechanisms.
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Affiliation(s)
- Jiacheng Yu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Gang Chen
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Hua Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Yi Zhong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Zhenxing Yang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Zhihong Jian
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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Cossard A, Stam K, Smets A, Jossin Y. MKL/SRF and Bcl6 mutual transcriptional repression safeguards the fate and positioning of neocortical progenitor cells mediated by RhoA. SCIENCE ADVANCES 2023; 9:eadd0676. [PMID: 37967194 PMCID: PMC10651131 DOI: 10.1126/sciadv.add0676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 10/16/2023] [Indexed: 11/17/2023]
Abstract
During embryogenesis, multiple intricate and intertwined cellular signaling pathways coordinate cell behavior. Their slightest alterations can have dramatic consequences for the cells and the organs they form. The transcriptional repressor Bcl6 was recently found as important for brain development. However, its regulation and integration with other signals is unknown. Using in vivo functional approaches combined with molecular mechanistic analysis, we identified a reciprocal regulatory loop between B cell lymphoma 6 (Bcl6) and the RhoA-regulated transcriptional complex megakaryoblastic leukemia/serum response factor (MKL/SRF). We show that Bcl6 physically interacts with MKL/SRF, resulting in a down-regulation of the transcriptional activity of both Bcl6 and MKL/SRF. This molecular cross-talk is essential for the control of proliferation, neurogenesis, and spatial positioning of neural progenitors. Overall, our data highlight a regulatory mechanism that controls neuronal production and neocortical development and reveal an MKL/SRF and Bcl6 interaction that may have broader implications in other physiological functions and in diseases.
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Affiliation(s)
- Alexia Cossard
- Laboratory of Mammalian Development and Cell Biology, Institute of Neuroscience, Université Catholique de Louvain, Brussels 1200, Belgium
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12
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Zeng X, Zhao F, Jia J, Ma X, Jiang Q, Zhang R, Li C, Wang T, Liu W, Hao Y, Tao K, Lou Z, Zhang P. Targeting BCL6 in Gastrointestinal Stromal Tumor Promotes p53-Mediated Apoptosis to Enhance the Antitumor Activity of Imatinib. Cancer Res 2023; 83:3624-3635. [PMID: 37556508 DOI: 10.1158/0008-5472.can-23-0082] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 05/21/2023] [Accepted: 08/04/2023] [Indexed: 08/11/2023]
Abstract
Imatinib mesylate (IM) has revolutionized the treatment of gastrointestinal stromal tumor (GIST). However, most patients inevitably acquire IM resistance. Second- and third-line treatments exhibit modest clinical benefits with a median time to disease progression of 4 to 6 months, highlighting the urgency for novel therapeutic approaches. Here, we report that the expression of BCL6, a known oncogenic driver and transcriptional repressor, was significantly induced in GIST cells following IM treatment. Elevated BCL6 levels suppressed apoptosis and contributed to IM resistance. Mechanistically, BCL6 recruited SIRT1 to the TP53 promoter to modulate histone acetylation and transcriptionally repress TP53 expression. The reduction in p53 subsequently attenuated cell apoptosis and promoted tolerance of GIST cells to IM. Concordantly, treatment of GIST cells showing high BCL6 expression with a BCL6 inhibitor, BI-3802, conferred IM sensitivity. Furthermore, BI-3802 showed striking synergy with IM in IM-responsive and IM-resistant GIST cells in vitro and in vivo. Thus, these findings reveal a role for BCL6 in IM resistance and suggest that a combination of BCL6 inhibitors and IM could be a potentially effective treatment for GIST. SIGNIFICANCE BCL6 drives resistance to imatinib by inhibiting p53-mediated apoptosis and can be targeted in combination with imatinib to synergistically suppress tumor growth, providing a therapeutic strategy for treating gastrointestinal stromal tumor.
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Affiliation(s)
- Xiangyu Zeng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fei Zhao
- College of Biology, Hunan University, Changsha, China
| | - Jie Jia
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xianxiong Ma
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Jiang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruizhi Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengguo Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weizhen Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yalan Hao
- Analytical Instrumentation Center, Hunan University, Changsha, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenkun Lou
- Department of Oncology, Mayo Clinic, Rochester, Minnesota
| | - Peng Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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13
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Shabani K, Pigeon J, Benaissa Touil Zariouh M, Liu T, Saffarian A, Komatsu J, Liu E, Danda N, Becmeur-Lefebvre M, Limame R, Bohl D, Parras C, Hassan BA. The temporal balance between self-renewal and differentiation of human neural stem cells requires the amyloid precursor protein. SCIENCE ADVANCES 2023; 9:eadd5002. [PMID: 37327344 PMCID: PMC10275593 DOI: 10.1126/sciadv.add5002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 05/11/2023] [Indexed: 06/18/2023]
Abstract
Neurogenesis in the developing human cerebral cortex occurs at a particularly slow rate owing in part to cortical neural progenitors preserving their progenitor state for a relatively long time, while generating neurons. How this balance between the progenitor and neurogenic state is regulated, and whether it contributes to species-specific brain temporal patterning, is poorly understood. Here, we show that the characteristic potential of human neural progenitor cells (NPCs) to remain in a progenitor state as they generate neurons for a prolonged amount of time requires the amyloid precursor protein (APP). In contrast, APP is dispensable in mouse NPCs, which undergo neurogenesis at a much faster rate. Mechanistically, APP cell-autonomously contributes to protracted neurogenesis through suppression of the proneurogenic activator protein-1 transcription factor and facilitation of canonical WNT signaling. We propose that the fine balance between self-renewal and differentiation is homeostatically regulated by APP, which may contribute to human-specific temporal patterns of neurogenesis.
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Affiliation(s)
- Khadijeh Shabani
- Institut du Cerveau–Paris Brain Institute–ICM, Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Julien Pigeon
- Institut du Cerveau–Paris Brain Institute–ICM, Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Marwan Benaissa Touil Zariouh
- Institut du Cerveau–Paris Brain Institute–ICM, Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Tengyuan Liu
- Institut du Cerveau–Paris Brain Institute–ICM, Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Azadeh Saffarian
- Scipio bioscience, iPEPS-ICM, Hôpital Pitié-Salpêtrière, Paris, France
| | - Jun Komatsu
- Scipio bioscience, iPEPS-ICM, Hôpital Pitié-Salpêtrière, Paris, France
| | - Elise Liu
- Institut du Cerveau–Paris Brain Institute–ICM, Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Natasha Danda
- Institut du Cerveau–Paris Brain Institute–ICM, Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Mathilde Becmeur-Lefebvre
- Genetics and Foetopathology, Centre Hospitalier Regional d’Orleans–Hôpital de la Source, Orleans, France
| | - Ridha Limame
- Institut du Cerveau–Paris Brain Institute–ICM, Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Delphine Bohl
- Institut du Cerveau–Paris Brain Institute–ICM, Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Carlos Parras
- Institut du Cerveau–Paris Brain Institute–ICM, Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Bassem A. Hassan
- Institut du Cerveau–Paris Brain Institute–ICM, Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
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14
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Li Y, Zhu Y, Chen L, Xia S, Adegboro AA, Wanggou S, Li X. Transcription factor ZBTB42 is a novel prognostic factor associated with immune cell infiltration in glioma. Front Pharmacol 2023; 14:1102277. [PMID: 36762114 PMCID: PMC9905726 DOI: 10.3389/fphar.2023.1102277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 01/16/2023] [Indexed: 01/26/2023] Open
Abstract
Background: ZBTB42 is a transcription factor that belongs to the ZBTB transcript factor family and plays an important role in skeletal muscle development. Dysregulation of ZBTB42 expression can lead to a variety of diseases. However, the function of ZBTB42 in glioma development has not been studied by now. Methods: We analyzed the expression of ZBTB42 in LGG and GBM via the The Cancer Genome Atlas CGA and Chinese Glioma Genome Atlas database. Gene Ontology, KEGG, and GSVA analyses were performed to illustrate ZBTB42-related pathways. ESTIMATE and CIBERSORT were applied to calculate the immune score and immune cell proportion in glioma. One-class logistic regression OCLR algorithm was used to study the stemness of glioma. Multivariate Cox analysis was employed to detect the prognostic value of five ZBTB42-related genes. Results: Our results show that ZBTB42 is highly expressed in glioma and may be a promising prognostic factor for Low Grade Glioma and GBM. In addition, ZBTB42 is related to immune cell infiltration and may play a role in the immune suppression microenvironment. What's more, ZBTB42 is correlated with stem cell markers and positively associated with glioma stemness. Finally, a five genes nomogram based on ZBTB42 was constructed and has an effective prognosis prediction ability. Conclusion: We identify that ZBTB42 is a prognostic biomarker for Low Grade Glioma and GBM and its function is related to the suppressive tumor microenvironment and stemness of glioma.
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Affiliation(s)
- Yanwen Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China,Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, China
| | - Yongwei Zhu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China,Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Yongwei Zhu, ; Xuejun Li,
| | - Long Chen
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China,Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, China
| | - Shunjin Xia
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China,Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, China
| | - Abraham Ayodeji Adegboro
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China,Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, China
| | - Siyi Wanggou
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China,Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, China
| | - Xuejun Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China,Hunan International Scientific and Technological Cooperation Base of Brain Tumor Research, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Yongwei Zhu, ; Xuejun Li,
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15
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Van Heurck R, Bonnefont J, Wojno M, Suzuki IK, Velez-Bravo FD, Erkol E, Nguyen DT, Herpoel A, Bilheu A, Beckers S, Ledent C, Vanderhaeghen P. CROCCP2 acts as a human-specific modifier of cilia dynamics and mTOR signaling to promote expansion of cortical progenitors. Neuron 2023; 111:65-80.e6. [PMID: 36334595 PMCID: PMC9831670 DOI: 10.1016/j.neuron.2022.10.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/12/2022] [Accepted: 10/09/2022] [Indexed: 11/06/2022]
Abstract
The primary cilium is a central signaling component during embryonic development. Here we focus on CROCCP2, a hominid-specific gene duplicate from ciliary rootlet coiled coil (CROCC), also known as rootletin, that encodes the major component of the ciliary rootlet. We find that CROCCP2 is highly expressed in the human fetal brain and not in other primate species. CROCCP2 gain of function in the mouse embryonic cortex and human cortical cells and organoids results in decreased ciliogenesis and increased cortical progenitor amplification, particularly basal progenitors. CROCCP2 decreases ciliary dynamics by inhibition of the IFT20 ciliary trafficking protein, which then impacts neurogenesis through increased mTOR signaling. Loss of function of CROCCP2 in human cortical cells and organoids leads to increased ciliogenesis, decreased mTOR signaling, and impaired basal progenitor amplification. These data identify CROCCP2 as a human-specific modifier of cortical neurogenesis that acts through modulation of ciliary dynamics and mTOR signaling.
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Affiliation(s)
- Roxane Van Heurck
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium,Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium,Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Jérôme Bonnefont
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium,Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium,Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Marta Wojno
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium,Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium,Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Ikuo K. Suzuki
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium,Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium,Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium,Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Fausto D. Velez-Bravo
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium,Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium,Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Emir Erkol
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium,Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium,Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Dan Truc Nguyen
- Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Adèle Herpoel
- Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Angéline Bilheu
- Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Sofie Beckers
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium,Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium
| | - Catherine Ledent
- Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Pierre Vanderhaeghen
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium,Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium,Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium,Corresponding author
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16
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Kabir F, Atkinson R, Cook AL, Phipps AJ, King AE. The role of altered protein acetylation in neurodegenerative disease. Front Aging Neurosci 2023; 14:1025473. [PMID: 36688174 PMCID: PMC9845957 DOI: 10.3389/fnagi.2022.1025473] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/03/2022] [Indexed: 01/06/2023] Open
Abstract
Acetylation is a key post-translational modification (PTM) involved in the regulation of both histone and non-histone proteins. It controls cellular processes such as DNA transcription, RNA modifications, proteostasis, aging, autophagy, regulation of cytoskeletal structures, and metabolism. Acetylation is essential to maintain neuronal plasticity and therefore essential for memory and learning. Homeostasis of acetylation is maintained through the activities of histone acetyltransferases (HAT) and histone deacetylase (HDAC) enzymes, with alterations to these tightly regulated processes reported in several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Both hyperacetylation and hypoacetylation can impair neuronal physiological homeostasis and increase the accumulation of pathophysiological proteins such as tau, α-synuclein, and Huntingtin protein implicated in AD, PD, and HD, respectively. Additionally, dysregulation of acetylation is linked to impaired axonal transport, a key pathological mechanism in ALS. This review article will discuss the physiological roles of protein acetylation and examine the current literature that describes altered protein acetylation in neurodegenerative disorders.
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17
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Surya K, Manickam N, Jayachandran KS, Kandasamy M, Anusuyadevi M. Resveratrol Mediated Regulation of Hippocampal Neuroregenerative Plasticity via SIRT1 Pathway in Synergy with Wnt Signaling: Neurotherapeutic Implications to Mitigate Memory Loss in Alzheimer's Disease. J Alzheimers Dis 2023; 94:S125-S140. [PMID: 36463442 PMCID: PMC10473144 DOI: 10.3233/jad-220559] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Alzheimer's disease (AD) is a major form of dementia. Abnormal amyloidogenic event-mediated degeneration of cholinergic neurons in the cognitive centers of the brain has been attributed to neuropathological sequelae and behavioral deficits in AD. Besides, impaired adult neurogenesis in the hippocampus has experimentally been realized as an underlying cause of dementia regardless of neurodegeneration. Therefore, nourishing the neurogenic process in the hippocampus has been considered an effective therapeutic strategy to mitigate memory loss. In the physiological state, the Wnt pathway has been identified as a potent mitogenic generator in the hippocampal stem cell niche. However, downstream components of Wnt signaling have been noticed to be downregulated in AD brains. Resveratrol (RSV) is a potent Sirtuin1 (SIRT1) enhancer that facilitates neuroprotection and promotes neurogenesis in the hippocampus of the adult brain. While SIRT1 is an important positive regulator of Wnt signaling, ample reports indicate that RSV treatment strongly mediates the fate determination of stem cells through Wnt signaling. However, the possible therapeutic roles of RSV-mediated SIRT1 enhancement on the regulation of hippocampal neurogenesis and reversal of memory loss through the Wnt signaling pathway have not been addressed yet. Taken together, this review describes RSV-mediated effects on the regulation of hippocampal neurogenesis via the activation of SIRT1 in synergy with the Wnt signaling. Further, the article emphasizes a hypothesis that RSV treatment can provoke the activation of quiescent neural stem cells and prime their neurogenic capacity in the hippocampus via Wnt signaling in AD.
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Affiliation(s)
- Kumar Surya
- Department of Biochemistry, Molecular Neuro-gerontology Laboratory, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Nivethitha Manickam
- Department of Animal Science, Laboratory of Stem Cells and Neuroregeneration, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Kesavan Swaminathan Jayachandran
- Department of Bioinformatics, Molecular Cardiology and Drug Discovery Laboratory, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Mahesh Kandasamy
- Department of Animal Science, Laboratory of Stem Cells and Neuroregeneration, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
- University Grants Commission-Faculty Recharge Programme (UGC-FRP), New Delhi, India
| | - Muthuswamy Anusuyadevi
- Department of Biochemistry, Molecular Neuro-gerontology Laboratory, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
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18
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Petridi S, Dubal D, Rikhy R, van den Ameele J. Mitochondrial respiration and dynamics of in vivo neural stem cells. Development 2022; 149:285126. [PMID: 36445292 PMCID: PMC10112913 DOI: 10.1242/dev.200870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Neural stem cells (NSCs) in the developing and adult brain undergo many different transitions, tightly regulated by extrinsic and intrinsic factors. While the role of signalling pathways and transcription factors is well established, recent evidence has also highlighted mitochondria as central players in NSC behaviour and fate decisions. Many aspects of cellular metabolism and mitochondrial biology change during NSC transitions, interact with signalling pathways and affect the activity of chromatin-modifying enzymes. In this Spotlight, we explore recent in vivo findings, primarily from Drosophila and mammalian model systems, about the role that mitochondrial respiration and morphology play in NSC development and function.
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Affiliation(s)
- Stavroula Petridi
- Department of Clinical Neurosciences and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK
| | - Dnyanesh Dubal
- Department of Clinical Neurosciences and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK.,Biology, Indian Institute of Science Education and Research, Homi Bhabha Road, Pashan, Pune 411008, India
| | - Richa Rikhy
- Biology, Indian Institute of Science Education and Research, Homi Bhabha Road, Pashan, Pune 411008, India
| | - Jelle van den Ameele
- Department of Clinical Neurosciences and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK
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19
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Wiegreffe C, Wahl T, Joos NS, Bonnefont J, Liu P, Britsch S. Developmental cell death of cortical projection neurons is controlled by a Bcl11a/Bcl6‐dependent pathway. EMBO Rep 2022; 23:e54104. [PMID: 35766181 PMCID: PMC9346488 DOI: 10.15252/embr.202154104] [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: 10/06/2021] [Revised: 05/31/2022] [Accepted: 06/08/2022] [Indexed: 12/05/2022] Open
Abstract
Developmental neuron death plays a pivotal role in refining organization and wiring during neocortex formation. Aberrant regulation of this process results in neurodevelopmental disorders including impaired learning and memory. Underlying molecular pathways are incompletely determined. Loss of Bcl11a in cortical projection neurons induces pronounced cell death in upper‐layer cortical projection neurons during postnatal corticogenesis. We use this genetic model to explore genetic mechanisms by which developmental neuron death is controlled. Unexpectedly, we find Bcl6, previously shown to be involved in the transition of cortical neurons from progenitor to postmitotic differentiation state to provide a major checkpoint regulating neuron survival during late cortical development. We show that Bcl11a is a direct transcriptional regulator of Bcl6. Deletion of Bcl6 exerts death of cortical projection neurons. In turn, reintroduction of Bcl6 into Bcl11a mutants prevents induction of cell death in these neurons. Together, our data identify a novel Bcl11a/Bcl6‐dependent molecular pathway in regulation of developmental cell death during corticogenesis.
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Affiliation(s)
| | - Tobias Wahl
- Institute of Molecular and Cellular Anatomy Ulm University Ulm Germany
| | | | - Jerome Bonnefont
- Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI) Université Libre de Bruxelles (ULB) Brussels Belgium
- VIB‐KU Leuven Center for Brain & Disease Research, KU Leuven Department of Neuroscience Leuven Brain Institute Leuven Belgium
| | - Pentao Liu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong China
| | - Stefan Britsch
- Institute of Molecular and Cellular Anatomy Ulm University Ulm Germany
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20
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Zhang M, Liu Y, Shi L, Fang L, Xu L, Cao Y. Neural stemness unifies cell tumorigenicity and pluripotent differentiation potential. J Biol Chem 2022; 298:102106. [PMID: 35671824 PMCID: PMC9254501 DOI: 10.1016/j.jbc.2022.102106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 11/16/2022] Open
Abstract
Neural stemness is suggested to be the ground state of tumorigenicity and pluripotent differentiation potential. However, the relationship between these cell properties is unclear. Here, by disrupting the neural regulatory network in neural stem and cancer cells and by serial transplantation of cancer cells, we show that tumorigenicity and pluripotent differentiation potential are coupled cell properties unified by neural stemness. We show that loss of neural stemness via inhibition of SETDB1, an oncoprotein with enriched expression in embryonic neural cells during vertebrate embryogenesis, led to neuronal differentiation with reduced tumorigenicity and pluripotent differentiation potential in neural stem and cancer cells, whereas enhancement of neural stemness by SETDB1 overexpression caused the opposite effects. SETDB1 maintains a regulatory network comprising proteins involved in developmental programs and basic cellular functional machineries, including epigenetic modifications (EZH2), ribosome biogenesis (RPS3), translation initiation (EIF4G), and spliceosome assembly (SF3B1); all of these proteins are enriched in embryonic neural cells and play active roles in cancers. In addition, SETDB1 represses the transcription of genes promoting differentiation and cell cycle and growth arrest. Serial transplantation of cancer cells showed that neural stemness, tumorigenicity, and pluripotent differentiation potential were simultaneously enhanced; these effects were accompanied by increased expression of proteins involved in developmental programs and basic machineries, including SETDB1 and the abovementioned proteins, as well as by increased alternative splicing events. These results indicate that basic machineries work together to define a highly proliferative state with pluripotent differentiation potential and also suggest that neural stemness unifies tumorigenicity and differentiation potential.
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Affiliation(s)
- Min Zhang
- Shenzhen Research Institute of Nanjing University, Shenzhen, China; MOE Key Laboratory of Model Animals for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center of Medical School
| | - Yang Liu
- Shenzhen Research Institute of Nanjing University, Shenzhen, China; MOE Key Laboratory of Model Animals for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center of Medical School
| | - Lihua Shi
- MOE Key Laboratory of Model Animals for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center of Medical School
| | - Lei Fang
- Jiangsu Key Laboratory of Molecular Medicine of Medical School, Nanjing University, Nanjing, China
| | - Liyang Xu
- MOE Key Laboratory of Model Animals for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center of Medical School
| | - Ying Cao
- Shenzhen Research Institute of Nanjing University, Shenzhen, China; MOE Key Laboratory of Model Animals for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center of Medical School.
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21
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Romero-Morales AI, Gama V. Revealing the Impact of Mitochondrial Fitness During Early Neural Development Using Human Brain Organoids. Front Mol Neurosci 2022; 15:840265. [PMID: 35571368 PMCID: PMC9102998 DOI: 10.3389/fnmol.2022.840265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
Mitochondrial homeostasis -including function, morphology, and inter-organelle communication- provides guidance to the intrinsic developmental programs of corticogenesis, while also being responsive to environmental and intercellular signals. Two- and three-dimensional platforms have become useful tools to interrogate the capacity of cells to generate neuronal and glia progeny in a background of metabolic dysregulation, but the mechanistic underpinnings underlying the role of mitochondria during human neurogenesis remain unexplored. Here we provide a concise overview of cortical development and the use of pluripotent stem cell models that have contributed to our understanding of mitochondrial and metabolic regulation of early human brain development. We finally discuss the effects of mitochondrial fitness dysregulation seen under stress conditions such as metabolic dysregulation, absence of developmental apoptosis, and hypoxia; and the avenues of research that can be explored with the use of brain organoids.
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Affiliation(s)
| | - Vivian Gama
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, United States
- Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, United States
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, United States
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22
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Reduced chromatin accessibility correlates with resistance to Notch activation. Nat Commun 2022; 13:2210. [PMID: 35468895 PMCID: PMC9039071 DOI: 10.1038/s41467-022-29834-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 03/18/2022] [Indexed: 11/08/2022] Open
Abstract
The Notch signalling pathway is a master regulator of cell fate transitions in development and disease. In the brain, Notch promotes neural stem cell (NSC) proliferation, regulates neuronal migration and maturation and can act as an oncogene or tumour suppressor. How NOTCH and its transcription factor RBPJ activate distinct gene regulatory networks in closely related cell types in vivo remains to be determined. Here we use Targeted DamID (TaDa), requiring only thousands of cells, to identify NOTCH and RBPJ binding in NSCs and their progeny in the mouse embryonic cerebral cortex in vivo. We find that NOTCH and RBPJ associate with a broad network of NSC genes. Repression of NSC-specific Notch target genes in intermediate progenitors and neurons correlates with decreased chromatin accessibility, suggesting that chromatin compaction may contribute to restricting NOTCH-mediated transactivation.
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23
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Zheng ZY, Jiang T, Huang ZF, Chu B, Gu J, Zhao X, Liu H, Fan J, Yu LP, Jiang SH, Li Q, Hu LP, Kong FQ, Zhang L, Chen Q, Chen J, Zhang HW, Yin GY, Zhao SJ. Fatty acids derived from apoptotic chondrocytes fuel macrophages FAO through MSR1 for facilitating BMSCs osteogenic differentiation. Redox Biol 2022; 53:102326. [PMID: 35525025 PMCID: PMC9093016 DOI: 10.1016/j.redox.2022.102326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/18/2022] [Accepted: 04/27/2022] [Indexed: 11/15/2022] Open
Abstract
The nonunion following a fracture is associated with severe patient morbidity and economic consequences. Currently, accumulating studies are focusing on the importance of macrophages during fracture repair. However, details regarding the process by which macrophages facilitate endochondral ossification (EO) are largely unknown. In this study, we present evidence that apoptotic chondrocytes (ACs) are not inert corpses awaiting removal, but positively modulate the osteoinductive ability of macrophages. In vivo experiments revealed that fatty acid (FA) metabolic processes up-regulated following EO. In vitro studies further uncovered that FAs derived from ACs are taken up by macrophages mainly through macrophage scavenger receptor 1 (MSR1). Then, our functional experiments confirmed that these exogenous FAs subsequently activate peroxisome proliferator-activated receptor α (PPARα), which further facilitates lipid droplets generation and fatty acid oxidation (FAO). Mechanistically, elevated FAO is involved in up-regulating the osteoinductive effect by generating BMP7 and NAD+/SIRT1/EZH2 axis epigenetically controls BMP7 expression in macrophages cultured with ACs culture medium. Our findings advanced the concept that ACs could promote bone regeneration by regulating metabolic and function reprogram in macrophages and identified macrophage MSR1 represents a valuable target for fracture treatments.
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24
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Kang X, Zhang ZP, Song CG, Liu L, Zhao Y, Du JL, Lai YB, Cao XL, Ye WM, Zhang YF, Zheng MH, Zeng YH, Sun XL, Wu SX, Gao F. γ-secretase inhibitor disturbs the morphological development of differentiating neurons through affecting Notch/miR-342-5p. Neurosci Lett 2022; 778:136603. [DOI: 10.1016/j.neulet.2022.136603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 03/21/2022] [Accepted: 03/26/2022] [Indexed: 10/18/2022]
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25
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Wade AA, van den Ameele J, Cheetham SW, Yakob R, Brand AH, Nord AS. In vivo targeted DamID identifies CHD8 genomic targets in fetal mouse brain. iScience 2021; 24:103234. [PMID: 34746699 PMCID: PMC8551073 DOI: 10.1016/j.isci.2021.103234] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 08/11/2021] [Accepted: 10/04/2021] [Indexed: 01/15/2023] Open
Abstract
Genetic studies of autism have revealed causal roles for chromatin remodeling gene mutations. Chromodomain helicase DNA binding protein 8 (CHD8) encodes a chromatin remodeler with significant de novo mutation rates in sporadic autism. However, relationships between CHD8 genomic function and autism-relevant biology remain poorly elucidated. Published studies utilizing ChIP-seq to map CHD8 protein-DNA interactions have high variability, consistent with technical challenges and limitations associated with this method. Thus, complementary approaches are needed to establish CHD8 genomic targets and regulatory functions in developing brain. We used in utero CHD8 Targeted DamID followed by sequencing (TaDa-seq) to characterize CHD8 binding in embryonic mouse cortex. CHD8 TaDa-seq reproduced interaction patterns observed from ChIP-seq and further highlighted CHD8 distal interactions associated with neuronal loci. This study establishes TaDa-seq as a useful alternative for mapping protein-DNA interactions in vivo and provides insights into the regulatory targets of CHD8 and autism-relevant pathophysiology associated with CHD8 mutations.
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Affiliation(s)
- A. Ayanna Wade
- Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA 95616, USA
- Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA 95616, USA
| | - Jelle van den Ameele
- The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 1TN, UK
| | - Seth W. Cheetham
- The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 1TN, UK
| | - Rebecca Yakob
- The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 1TN, UK
| | - Andrea H. Brand
- The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 1TN, UK
| | - Alex S. Nord
- Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA 95616, USA
- Department of Neurobiology, Physiology and Behavior, University of California, Davis, Davis, CA 95616, USA
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26
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Engel-Pizcueta C, Pujades C. Interplay Between Notch and YAP/TAZ Pathways in the Regulation of Cell Fate During Embryo Development. Front Cell Dev Biol 2021; 9:711531. [PMID: 34490262 PMCID: PMC8417249 DOI: 10.3389/fcell.2021.711531] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/02/2021] [Indexed: 12/23/2022] Open
Abstract
Cells in growing tissues receive both biochemical and physical cues from their microenvironment. Growing evidence has shown that mechanical signals are fundamental regulators of cell behavior. However, how physical properties of the microenvironment are transduced into critical cell behaviors, such as proliferation, progenitor maintenance, or differentiation during development, is still poorly understood. The transcriptional co-activators YAP/TAZ shuttle between the cytoplasm and the nucleus in response to multiple inputs and have emerged as important regulators of tissue growth and regeneration. YAP/TAZ sense and transduce physical cues, such as those from the extracellular matrix or the actomyosin cytoskeleton, to regulate gene expression, thus allowing them to function as gatekeepers of progenitor behavior in several developmental contexts. The Notch pathway is a key signaling pathway that controls binary cell fate decisions through cell-cell communication in a context-dependent manner. Recent reports now suggest that the crosstalk between these two pathways is critical for maintaining the balance between progenitor maintenance and cell differentiation in different tissues. How this crosstalk integrates with morphogenesis and changes in tissue architecture during development is still an open question. Here, we discuss how progenitor cell proliferation, specification, and differentiation are coordinated with morphogenesis to construct a functional organ. We will pay special attention to the interplay between YAP/TAZ and Notch signaling pathways in determining cell fate decisions and discuss whether this represents a general mechanism of regulating cell fate during development. We will focus on research carried out in vertebrate embryos that demonstrate the important roles of mechanical cues in stem cell biology and discuss future challenges.
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Affiliation(s)
- Carolyn Engel-Pizcueta
- Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Cristina Pujades
- Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
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27
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Synthetic modified Fezf2 mRNA (modRNA) with concurrent small molecule SIRT1 inhibition enhances refinement of cortical subcerebral/corticospinal neuron identity from mouse embryonic stem cells. PLoS One 2021; 16:e0254113. [PMID: 34473715 PMCID: PMC8412356 DOI: 10.1371/journal.pone.0254113] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/20/2021] [Indexed: 01/29/2023] Open
Abstract
During late embryonic development of the cerebral cortex, the major class of cortical output neurons termed subcerebral projection neurons (SCPN; including the predominant population of corticospinal neurons, CSN) and the class of interhemispheric callosal projection neurons (CPN) initially express overlapping molecular controls that later undergo subtype-specific refinements. Such molecular refinements are largely absent in heterogeneous, maturation-stalled, neocortical-like neurons (termed "cortical" here) spontaneously generated by established embryonic stem cell (ES) and induced pluripotent stem cell (iPSC) differentiation. Building on recently identified central molecular controls over SCPN development, we used a combination of synthetic modified mRNA (modRNA) for Fezf2, the central transcription factor controlling SCPN specification, and small molecule screening to investigate whether distinct chromatin modifiers might complement Fezf2 functions to promote SCPN-specific differentiation by mouse ES (mES)-derived cortical-like neurons. We find that the inhibition of a specific histone deacetylase, Sirtuin 1 (SIRT1), enhances refinement of SCPN subtype molecular identity by both mES-derived cortical-like neurons and primary dissociated E12.5 mouse cortical neurons. In vivo, we identify that SIRT1 is specifically expressed by CPN, but not SCPN, during late embryonic and postnatal differentiation. Together, these data indicate that SIRT1 has neuronal subtype-specific expression in the mouse cortex in vivo, and that its inhibition enhances subtype-specific differentiation of highly clinically relevant SCPN / CSN cortical neurons in vitro.
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28
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Iwata R. Temporal differences of neurodevelopment processes between species. Neurosci Res 2021; 177:8-15. [PMID: 34419562 DOI: 10.1016/j.neures.2021.08.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/08/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023]
Abstract
The ontogeny programs are highly conserved across all vertebrates, although there are significant temporal variations in interspecies developmental processes. Changing the timing and rate of developmental processes could affect subsequent organogenesis profoundly and may also have been critical factors in evolutionary diversity. However, despite their potential importance, the cellular and molecular mechanisms that control interspecies differences in developmental timescale remain unclear. This review highlights recent advances in the experimental models to compare interspecies differences in neurodevelopmental processes, neurogenesis, and neuronal maturation and discusses the possible mechanisms that could generate species-specific timescales.
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Affiliation(s)
- Ryohei Iwata
- VIB KU Leuven Center for Brain & Disease Research, KU Leuven Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium; Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium.
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29
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Iwata R, Vanderhaeghen P. Regulatory roles of mitochondria and metabolism in neurogenesis. Curr Opin Neurobiol 2021; 69:231-240. [PMID: 34171617 PMCID: PMC8415079 DOI: 10.1016/j.conb.2021.05.003] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/14/2021] [Accepted: 05/18/2021] [Indexed: 01/14/2023]
Abstract
Neural stem cells (NSCs) undergo massive molecular and cellular changes during neuronal differentiation. These include mitochondria and metabolism remodelling, which were thought to be mostly permissive cues, but recent work indicates that they are causally linked to neurogenesis. Striking remodelling of mitochondria occurs right after mitosis of NSCs, which influences the postmitotic daughter cells towards self-renewal or differentiation. The transitioning to neuronal fate requires metabolic rewiring including increased oxidative phosphorylation activity, which drives transcriptional and epigenetic effects to influence cell fate. Mitochondria metabolic pathways also contribute in an essential way to the regulation of NSC proliferation and self-renewal. The influence of mitochondria and metabolism on neurogenesis is conserved from fly to human systems, but also displays striking differences linked to cell context or species. These new findings have important implications for our understanding of neurodevelopmental diseases and possibly human brain evolution.
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Affiliation(s)
- Ryohei Iwata
- VIB KULeuven Center for Brain & Disease Research, KU Leuven Department of Neurosciences, Leuven Brain Institute, Leuven, 3000, Belgium; Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), ULB Neuroscience Institute (UNI), Brussels, 1070, Belgium
| | - Pierre Vanderhaeghen
- VIB KULeuven Center for Brain & Disease Research, KU Leuven Department of Neurosciences, Leuven Brain Institute, Leuven, 3000, Belgium; Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), ULB Neuroscience Institute (UNI), Brussels, 1070, Belgium.
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30
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Bedogni F, Hevner RF. Cell-Type-Specific Gene Expression in Developing Mouse Neocortex: Intermediate Progenitors Implicated in Axon Development. Front Mol Neurosci 2021; 14:686034. [PMID: 34321999 PMCID: PMC8313239 DOI: 10.3389/fnmol.2021.686034] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/03/2021] [Indexed: 01/06/2023] Open
Abstract
Cerebral cortex projection neurons (PNs) are generated from intermediate progenitors (IPs), which are in turn derived from radial glial progenitors (RGPs). To investigate developmental processes in IPs, we profiled IP transcriptomes in embryonic mouse neocortex, using transgenic Tbr2-GFP mice, cell sorting, and microarrays. These data were used in combination with in situ hybridization to ascertain gene sets specific for IPs, RGPs, PNs, interneurons, and other neural and non-neural cell types. RGP-selective transcripts (n = 419) included molecules for Notch receptor signaling, proliferation, neural stem cell identity, apical junctions, necroptosis, hippo pathway, and NF-κB pathway. RGPs also expressed specific genes for critical interactions with meningeal and vascular cells. In contrast, IP-selective genes (n = 136) encoded molecules for activated Delta ligand presentation, epithelial-mesenchymal transition, core planar cell polarity (PCP), axon genesis, and intrinsic excitability. Interestingly, IPs expressed several “dependence receptors” (Unc5d, Dcc, Ntrk3, and Epha4) that induce apoptosis in the absence of ligand, suggesting a competitive mechanism for IPs and new PNs to detect key environmental cues or die. Overall, our results imply a novel role for IPs in the patterning of neuronal polarization, axon differentiation, and intrinsic excitability prior to mitosis. Significantly, IPs highly express Wnt-PCP, netrin, and semaphorin pathway molecules known to regulate axon polarization in other systems. In sum, IPs not only amplify neurogenesis quantitatively, but also molecularly “prime” new PNs for axogenesis, guidance, and excitability.
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Affiliation(s)
| | - Robert F Hevner
- Department of Pathology, University of California, San Diego, La Jolla, CA, United States
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31
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Tay EXY, Chia K, Ong DST. Epigenetic plasticity and redox regulation of neural stem cell state and fate. Free Radic Biol Med 2021; 170:116-130. [PMID: 33684459 DOI: 10.1016/j.freeradbiomed.2021.02.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 01/20/2021] [Accepted: 02/24/2021] [Indexed: 12/16/2022]
Abstract
The neural stem cells (NSCs) are essential for normal brain development and homeostasis. The cell state (i.e. quiescent versus activated) and fate (i.e. the cell lineage of choice upon differentiation) of NSCs are tightly controlled by various redox and epigenetic regulatory mechanisms. There is an increasing appreciation that redox and epigenetic regulations are intimately linked, but how this redox-epigenetics crosstalk affects NSC activity remains poorly understood. Another unresolved topic is whether the NSCs actually contribute to brain ageing and neurodegenerative diseases. In this review, we aim to 1) distill concepts that underlie redox and epigenetic regulation of NSC state and fate; 2) provide examples of the redox-epigenetics crosstalk in NSC biology; and 3) highlight potential redox- and epigenetic-based therapeutic opportunities to rescue NSC dysfunctions in ageing and neurodegenerative diseases.
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Affiliation(s)
- Emmy Xue Yun Tay
- Department of Physiology, National University of Singapore, Singapore, 117593, Singapore
| | - Kimberly Chia
- Department of Physiology, National University of Singapore, Singapore, 117593, Singapore
| | - Derrick Sek Tong Ong
- Department of Physiology, National University of Singapore, Singapore, 117593, Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore; National Neuroscience Institute, Singapore, 308433, Singapore.
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32
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Ballabio C, Gianesello M, Lago C, Okonechnikov K, Anderle M, Aiello G, Antonica F, Zhang T, Gianno F, Giangaspero F, Hassan BA, Pfister SM, Tiberi L. Notch1 switches progenitor competence in inducing medulloblastoma. SCIENCE ADVANCES 2021; 7:7/26/eabd2781. [PMID: 34162555 PMCID: PMC8221631 DOI: 10.1126/sciadv.abd2781] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 05/07/2021] [Indexed: 05/13/2023]
Abstract
The identity of the cell of origin is a key determinant of cancer subtype, progression, and prognosis. Group 3 medulloblastoma (MB) is a malignant childhood brain cancer with poor prognosis and few candidates as putative cell of origin. We overexpressed the group 3 MB genetic drivers MYC and Gfi1 in different candidate cells of origin in the postnatal mouse cerebellum. We found that S100b+ cells are competent to initiate group 3 MB, and we observed that S100b+ cells have higher levels of Notch1 pathway activity compared to Math1+ cells. We found that additional activation of Notch1 in Math1+ and Sox2+ cells was sufficient to induce group 3 MB upon MYC/Gfi1 expression. Together, our data suggest that the Notch1 pathway plays a critical role in group 3 MB initiation.
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Affiliation(s)
- Claudio Ballabio
- Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
| | - Matteo Gianesello
- Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
| | - Chiara Lago
- Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
| | - Konstantin Okonechnikov
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany
| | - Marica Anderle
- Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
| | - Giuseppe Aiello
- Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
| | - Francesco Antonica
- Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
| | - Tingting Zhang
- Paris Brain Institute-Institut du Cerveau, Sorbonne Université, Inserm, CNRS, Hôpital Pitié-Salpêtrière, 8, Paris, France
| | - Francesca Gianno
- Dept. of Radiologic, Oncologic and Anatomo Pathological Sciences, University Sapienza of Rome, Rome, Italy
- IRCCS Neuromed, Pozzilli, Isernia, Italy
| | - Felice Giangaspero
- Dept. of Radiologic, Oncologic and Anatomo Pathological Sciences, University Sapienza of Rome, Rome, Italy
- IRCCS Neuromed, Pozzilli, Isernia, Italy
| | - Bassem A Hassan
- Paris Brain Institute-Institut du Cerveau, Sorbonne Université, Inserm, CNRS, Hôpital Pitié-Salpêtrière, 8, Paris, France
| | - Stefan M Pfister
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany
- Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Luca Tiberi
- Armenise-Harvard Laboratory of Brain Cancer, Department CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy.
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33
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Li J, Sun L, Peng XL, Yu XM, Qi SJ, Lu ZJ, Han JDJ, Shen Q. Integrative genomic analysis of early neurogenesis reveals a temporal genetic program for differentiation and specification of preplate and Cajal-Retzius neurons. PLoS Genet 2021; 17:e1009355. [PMID: 33760820 PMCID: PMC7990179 DOI: 10.1371/journal.pgen.1009355] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 01/12/2021] [Indexed: 01/02/2023] Open
Abstract
Neurogenesis in the developing neocortex begins with the generation of the preplate, which consists of early-born neurons including Cajal-Retzius (CR) cells and subplate neurons. Here, utilizing the Ebf2-EGFP transgenic mouse in which EGFP initially labels the preplate neurons then persists in CR cells, we reveal the dynamic transcriptome profiles of early neurogenesis and CR cell differentiation. Genome-wide RNA-seq and ChIP-seq analyses at multiple early neurogenic stages have revealed the temporal gene expression dynamics of early neurogenesis and distinct histone modification patterns in early differentiating neurons. We have identified a new set of coding genes and lncRNAs involved in early neuronal differentiation and validated with functional assays in vitro and in vivo. In addition, at E15.5 when Ebf2-EGFP+ cells are mostly CR neurons, single-cell sequencing analysis of purified Ebf2-EGFP+ cells uncovers molecular heterogeneities in CR neurons, but without apparent clustering of cells with distinct regional origins. Along a pseudotemporal trajectory these cells are classified into three different developing states, revealing genetic cascades from early generic neuronal differentiation to late fate specification during the establishment of CR neuron identity and function. Our findings shed light on the molecular mechanisms governing the early differentiation steps during cortical development, especially CR neuron differentiation. Neural stem cells and progenitor cells in the embryonic brain give rise to neurons following a precise temporal order after initial expansion. Early-born neurons including Cajal-Retzius (CR) cells and subplate neurons form the preplate in the developing cerebral cortex, then CR neurons occupy the layer 1, playing an important role in cortical histogenesis. The molecular mechanisms governing the early neuronal differentiation processes remain to be explored. Here, by genome-wide approaches including bulk RNA-seq, single-cell RNA-seq and ChIP-seq, we comprehensively characterized the temporal dynamic gene expression profile and epigenetic status at different stages during early cortical development and uncovered molecularly heterogeneous subpopulations within the CR cells. We revealed CR neuron signatures and cell type-specific histone modification patterns along early neuron specification. Using in vitro and in vivo assays, we identified novel lncRNAs as potential functional regulators in preplate differentiation and CR neuron identity establishment. Our study provides a comprehensive analysis of the genetic and epigenetic programs during neuronal differentiation and would help bring new insights into the early cortical neurogenesis process, particularly the differentiation of CR neurons.
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Affiliation(s)
- Jia Li
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- PTN graduate program, School of Life Sciences, Peking University, Beijing, China
- School of Medicine, Tsinghua University, Beijing, China
| | - Lei Sun
- PTN graduate program, School of Life Sciences, Tsinghua University, Beijing, China
| | | | - Xiao-Ming Yu
- School of Medicine, Tsinghua University, Beijing, China
| | - Shao-Jun Qi
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- School of Medicine, Tsinghua University, Beijing, China
| | - Zhi John Lu
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China
| | - Jing-Dong J. Han
- Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qin Shen
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Frontier Science Center for Stem Cell Research, Ministry of Education, School of Life Sciences and Technology, Tongji University, Shanghai, China
- Brain and Spinal Cord Clinical Research Center, Tongji University, Shanghai, China
- * E-mail:
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34
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Bonnefont J, Vanderhaeghen P. Neuronal fate acquisition and specification: time for a change. Curr Opin Neurobiol 2021; 66:195-204. [PMID: 33412482 PMCID: PMC8064025 DOI: 10.1016/j.conb.2020.12.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/03/2020] [Accepted: 12/08/2020] [Indexed: 12/15/2022]
Abstract
During embryonic development, neural stem/progenitor cells generate hundreds of different cell types through the combination of intrinsic and extrinsic cues. Recent data obtained in mouse and human cortical neurogenesis provide novel views about this interplay and how it evolves with time, whether during irreversible cell fate transitions that neural stem cells undergo to become neurons, or through gradual temporal changes of competence that lead to increased neuronal diversity from a common stem cell pool. In each case the temporal changes result from a dynamic balance between intracellular states and extracellular signalling factors. The underlying mechanisms are mostly conserved across species, but some display unique features in human corticogenesis, thereby linking temporal features of neurogenesis and human brain evolution.
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Affiliation(s)
- Jérôme Bonnefont
- Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium; VIB-KULeuven Center for Brain & Disease Research, KULeuven Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium.
| | - Pierre Vanderhaeghen
- Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium; VIB-KULeuven Center for Brain & Disease Research, KULeuven Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium.
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35
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Sirt1 Activity in the Brain: Simultaneous Effects on Energy Homeostasis and Reproduction. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18031243. [PMID: 33573212 PMCID: PMC7908627 DOI: 10.3390/ijerph18031243] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/21/2021] [Accepted: 01/25/2021] [Indexed: 12/14/2022]
Abstract
Diet deeply impacts brain functions like synaptic plasticity and cognitive processes, neuroendocrine functions, reproduction and behaviour, with detrimental or protective effects on neuronal physiology and therefore consequences for health. In this respect, the activity of metabolic sensors within the brain is critical for the maintenance of health status and represents a possible therapeutic target for some diseases. This review summarizes the main activity of Sirtuin1 (Sirt1), a metabolic sensor within the brain with a focus on the link between the central control of energy homeostasis and reproduction. The possible modulation of Sirt1 by natural phytochemical compounds like polyphenols is also discussed.
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36
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Kalafatakis I, Savvaki M, Velona T, Karagogeos D. Implication of Contactins in Demyelinating Pathologies. Life (Basel) 2021; 11:life11010051. [PMID: 33451101 PMCID: PMC7828632 DOI: 10.3390/life11010051] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/09/2021] [Accepted: 01/11/2021] [Indexed: 12/19/2022] Open
Abstract
Demyelinating pathologies comprise of a variety of conditions where either central or peripheral myelin is attacked, resulting in white matter lesions and neurodegeneration. Myelinated axons are organized into molecularly distinct domains, and this segregation is crucial for their proper function. These defined domains are differentially affected at the different stages of demyelination as well as at the lesion and perilesion sites. Among the main players in myelinated axon organization are proteins of the contactin (CNTN) group of the immunoglobulin superfamily (IgSF) of cell adhesion molecules, namely Contactin-1 and Contactin-2 (CNTN1, CNTN2). The two contactins perform their functions through intermolecular interactions, which are crucial for myelinated axon integrity and functionality. In this review, we focus on the implication of these two molecules as well as their interactors in demyelinating pathologies in humans. At first, we describe the organization and function of myelinated axons in the central (CNS) and the peripheral (PNS) nervous system, further analyzing the role of CNTN1 and CNTN2 as well as their interactors in myelination. In the last section, studies showing the correlation of the two contactins with demyelinating pathologies are reviewed, highlighting the importance of these recognition molecules in shaping the function of the nervous system in multiple ways.
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37
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Okado H. Nervous system regulated by POZ domain Krüppel-like zinc finger (POK) family transcription repressor RP58. Br J Pharmacol 2020; 178:813-826. [PMID: 32959890 DOI: 10.1111/bph.15265] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 08/07/2020] [Accepted: 08/31/2020] [Indexed: 12/21/2022] Open
Abstract
The POZ domain Krüppel-like zinc finger transcription repressor (POK family) contains many important molecules, including RP58, Bcl6 and PLZF. They function as transcription repressors via chromatin remodelling and histone deacetylation and are known to be involved in the development and tumourigenesis of various organs. Furthermore, they are important in the formation and function of the nervous system. This review summarizes the role of the POK family transcription repressors in the nervous system. We particularly targeted Rp58 (also known as Znf238, Znp238 and Zbtb18), a sequence-specific transcriptional repressor that is strongly expressed in developing glutamatergic projection neurons in the cerebral cortex. It regulates various physiological processes, including neuronal production, neuronal migration and neuronal maturation. Human studies suggest that reduced RP58 levels are involved in cognitive function impairment and brain tumour formation. This review particularly focuses on the mechanisms underlying RP58-mediated neuronal development and function. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc.
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Affiliation(s)
- Haruo Okado
- Laboratory of Neural Development, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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38
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Iwata R, Casimir P, Vanderhaeghen P. Mitochondrial dynamics in postmitotic cells regulate neurogenesis. Science 2020; 369:858-862. [PMID: 32792401 DOI: 10.1126/science.aba9760] [Citation(s) in RCA: 182] [Impact Index Per Article: 36.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 06/22/2020] [Indexed: 11/03/2022]
Abstract
The conversion of neural stem cells into neurons is associated with the remodeling of organelles, but whether and how this is causally linked to fate change is poorly understood. We examined and manipulated mitochondrial dynamics during mouse and human cortical neurogenesis. We reveal that shortly after cortical stem cells have divided, daughter cells destined to self-renew undergo mitochondrial fusion, whereas those that retain high levels of mitochondria fission become neurons. Increased mitochondria fission promotes neuronal fate, whereas induction of mitochondria fusion after mitosis redirects daughter cells toward self-renewal. This occurs during a restricted time window that is doubled in human cells, in line with their increased self-renewal capacity. Our data reveal a postmitotic period of fate plasticity in which mitochondrial dynamics are linked with cell fate.
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Affiliation(s)
- Ryohei Iwata
- VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.,Department of Neurosciences, Katholieke Universiteit (KU) Leuven, 3000 Leuven, Belgium.,Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium.,Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.,ULB Neuroscience Institute (UNI), ULB, 1070 Brussels, Belgium
| | - Pierre Casimir
- VIB Center for Brain and Disease Research, 3000 Leuven, Belgium.,Department of Neurosciences, Katholieke Universiteit (KU) Leuven, 3000 Leuven, Belgium.,Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium.,Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.,ULB Neuroscience Institute (UNI), ULB, 1070 Brussels, Belgium
| | - Pierre Vanderhaeghen
- VIB Center for Brain and Disease Research, 3000 Leuven, Belgium. .,Department of Neurosciences, Katholieke Universiteit (KU) Leuven, 3000 Leuven, Belgium.,Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium.,Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.,ULB Neuroscience Institute (UNI), ULB, 1070 Brussels, Belgium
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Li L, Maire CL, Bilenky M, Carles A, Heravi-Moussavi A, Hong C, Tam A, Kamoh B, Cho S, Cheung D, Li I, Wong T, Nagarajan RP, Mungall AJ, Moore R, Wang T, Kleinman CL, Jabado N, Jones SJM, Marra MA, Ligon KL, Costello JF, Hirst M. Epigenomic programming in early fetal brain development. Epigenomics 2020; 12:1053-1070. [PMID: 32677466 PMCID: PMC7857341 DOI: 10.2217/epi-2019-0319] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 03/19/2020] [Indexed: 12/21/2022] Open
Abstract
Aim: To provide a comprehensive understanding of gene regulatory networks in the developing human brain and a foundation for interpreting pathogenic deregulation. Materials & methods: We generated reference epigenomes and transcriptomes of dissected brain regions and primary neural progenitor cells (NPCs) derived from cortical and ganglionic eminence tissues of four normal human fetuses. Results: Integration of these data across developmental stages revealed a directional increase in active regulatory states, transcription factor activities and gene transcription with developmental stage. Consistent with differences in their biology, NPCs derived from cortical and ganglionic eminence regions contained common, region specific, and gestational week specific regulatory states. Conclusion: We provide a high-resolution regulatory network for NPCs from different brain regions as a comprehensive reference for future studies.
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Affiliation(s)
- Luolan Li
- Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - Cecile L Maire
- Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Misha Bilenky
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Annaïck Carles
- Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | | | - Chibo Hong
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94158, USA
| | - Angela Tam
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Baljit Kamoh
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Stephanie Cho
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Dorothy Cheung
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Irene Li
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Tina Wong
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Raman P Nagarajan
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94158, USA
| | - Andrew J Mungall
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Richard Moore
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Ting Wang
- Department of Genetics, Washington University, St Louis, MO 63108, USA
| | - Claudia L Kleinman
- Department of Human Genetics, McGill University, Montreal, QC, H3T 1E2, Canada
| | - Nada Jabado
- Department of Human Genetics, McGill University, Montreal, QC, H3T 1E2, Canada
| | - Steven JM Jones
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
| | - Marco A Marra
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 3N1, Canada
| | - Keith L Ligon
- Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Joseph F Costello
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94158, USA
| | - Martin Hirst
- Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
- Canada's Michael Smith Genome Science Center, BC Cancer, Vancouver, BC, V5Z 4S6, Canada
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40
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Yook C, Kim K, Kim D, Kang H, Kim SG, Kim E, Kim SY. A TBR1-K228E Mutation Induces Tbr1 Upregulation, Altered Cortical Distribution of Interneurons, Increased Inhibitory Synaptic Transmission, and Autistic-Like Behavioral Deficits in Mice. Front Mol Neurosci 2019; 12:241. [PMID: 31680851 PMCID: PMC6797848 DOI: 10.3389/fnmol.2019.00241] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 09/20/2019] [Indexed: 12/11/2022] Open
Abstract
Mutations in Tbr1, a high-confidence ASD (autism spectrum disorder)-risk gene encoding the transcriptional regulator TBR1, have been shown to induce diverse ASD-related molecular, synaptic, neuronal, and behavioral dysfunctions in mice. However, whether Tbr1 mutations derived from autistic individuals cause similar dysfunctions in mice remains unclear. Here we generated and characterized mice carrying the TBR1-K228E de novo mutation identified in human ASD and identified various ASD-related phenotypes. In heterozygous mice carrying this mutation (Tbr1+/K228E mice), levels of the TBR1-K228E protein, which is unable to bind target DNA, were strongly increased. RNA-Seq analysis of the Tbr1+/K228E embryonic brain indicated significant changes in the expression of genes associated with neurons, astrocytes, ribosomes, neuronal synapses, and ASD risk. The Tbr1+/K228E neocortex also displayed an abnormal distribution of parvalbumin-positive interneurons, with a lower density in superficial layers but a higher density in deep layers. These changes were associated with an increase in inhibitory synaptic transmission in layer 6 pyramidal neurons that was resistant to compensation by network activity. Behaviorally, Tbr1+/K228E mice showed decreased social interaction, increased self-grooming, and modestly increased anxiety-like behaviors. These results suggest that the human heterozygous TBR1-K228E mutation induces ASD-related transcriptomic, protein, neuronal, synaptic, and behavioral dysfunctions in mice.
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Affiliation(s)
- Chaehyun Yook
- Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, South Korea
| | - Kyungdeok Kim
- Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, South Korea
| | - Doyoun Kim
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, South Korea
| | - Hyojin Kang
- Division of National Supercomputing, Korea Institute of Science and Technology Information (KISTI), Daejeon, South Korea
| | - Sun-Gyun Kim
- Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, South Korea
| | - Eunjoon Kim
- Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, South Korea.,Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, South Korea
| | - Soo Young Kim
- College of Pharmacy, Yeongnam University, Gyeongsan, South Korea
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41
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Bonnefont J, Tiberi L, van den Ameele J, Potier D, Gaber ZB, Lin X, Bilheu A, Herpoel A, Velez Bravo FD, Guillemot F, Aerts S, Vanderhaeghen P. Cortical Neurogenesis Requires Bcl6-Mediated Transcriptional Repression of Multiple Self-Renewal-Promoting Extrinsic Pathways. Neuron 2019; 103:1096-1108.e4. [PMID: 31353074 PMCID: PMC6859502 DOI: 10.1016/j.neuron.2019.06.027] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 05/08/2019] [Accepted: 06/26/2019] [Indexed: 12/14/2022]
Abstract
During neurogenesis, progenitors switch from self-renewal to differentiation through the interplay of intrinsic and extrinsic cues, but how these are integrated remains poorly understood. Here, we combine whole-genome transcriptional and epigenetic analyses with in vivo functional studies to demonstrate that Bcl6, a transcriptional repressor previously reported to promote cortical neurogenesis, acts as a driver of the neurogenic transition through direct silencing of a selective repertoire of genes belonging to multiple extrinsic pathways promoting self-renewal, most strikingly the Wnt pathway. At the molecular level, Bcl6 represses its targets through Sirt1 recruitment followed by histone deacetylation. Our data identify a molecular logic by which a single cell-intrinsic factor represses multiple extrinsic pathways that favor self-renewal, thereby ensuring robustness of neuronal fate transition.
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Affiliation(s)
- Jerome Bonnefont
- Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium; VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium
| | - Luca Tiberi
- Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Jelle van den Ameele
- Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Delphine Potier
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium
| | | | - Xionghui Lin
- Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Angéline Bilheu
- Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Adèle Herpoel
- Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium
| | - Fausto D Velez Bravo
- Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium; VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium
| | | | - Stein Aerts
- VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium
| | - Pierre Vanderhaeghen
- Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), 1070 Brussels, Belgium; VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KU Leuven, 3000 Leuven, Belgium; Welbio, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium.
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42
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Bugler J, Kinstrie R, Scott MT, Vetrie D. Epigenetic Reprogramming and Emerging Epigenetic Therapies in CML. Front Cell Dev Biol 2019; 7:136. [PMID: 31380371 PMCID: PMC6652210 DOI: 10.3389/fcell.2019.00136] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 07/05/2019] [Indexed: 12/16/2022] Open
Abstract
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by BCR-ABL1, an oncogenic fusion gene arising from the Philadelphia chromosome. The development of tyrosine kinase inhibitors (TKIs) to overcome the constitutive tyrosine kinase activity of the BCR-ABL protein has dramatically improved disease management and patient outcomes over the past 20 years. However, the majority of patients are not cured and developing novel therapeutic strategies that target epigenetic processes are a promising avenue to improve cure rates. A number of epigenetic mechanisms are altered or reprogrammed during the development and progression of CML, resulting in alterations in histone modifications, DNA methylation and dysregulation of the transcriptional machinery. In this review these epigenetic alterations are examined and the potential of epigenetic therapies are discussed as a means of eradicating residual disease and offering a potential cure for CML in combination with current therapies.
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Affiliation(s)
| | | | | | - David Vetrie
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
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43
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Liu B, Zhang Q, Ke C, Xia Z, Luo C, Li Y, Guan X, Cao X, Xu Y, Zhao Y. Ginseng-Angelica-Sansheng-Pulvis Boosts Neurogenesis Against Focal Cerebral Ischemia-Induced Neurological Deficiency. Front Neurosci 2019; 13:515. [PMID: 31191223 PMCID: PMC6549519 DOI: 10.3389/fnins.2019.00515] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 05/06/2019] [Indexed: 01/04/2023] Open
Abstract
Background The traditional Chinese medicine Ginseng-Angelica-Shanseng-Pulvis (GASP) has been used to treat stroke for 300 years. This present study investigated if it can induce increases in neurogenesis following cerebral ischemic injury. Methods Rats following middle cerebral artery occlusion were orally treated with high, medium, and low doses of a standardized GASP extract. Results After 14 days, treatment with GASP improved regional blood flow and infarction volume by magnetic resonance imaging scanning, enhanced Ki67+ expression in the subventricular zone, increased brain-derived neurotrophic factor (BDNF) secretion, Nestin, and bone morphogenetic protein (BMP) 2/4 expressions in the hippocampus in a dose-dependent manner. Interestingly, low-dose treatment with GASP downregulated doublecortin and Notch1 expressions in the hippocampus, as well as upregulated glial fibrillary acidic protein expression in the subgranular zone and hairy and enhancer of split (Hes) 5 expression in the hippocampus, while treatment with middle and high doses of GASP reversed these results. Meanwhile, the consumed time was shortened in the basket test and the adhesive removal test and the spending time on exploring novel objects was prolonged by GASP treatment whose effects were more obvious at day 14 post-ischemia. Conclusion Our study demonstrates that treatment with GASP increases neurogenesis and ameliorates sensorimotor functions and recognition memory. We hypothesize that these effects are thought be mediated by an effect on the BMP2/4 pathway and Notch1/Hes5 signal. Due to its beneficial efficacy, GASP can be recognized as an alternative therapeutic agent for ischemic stroke.
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Affiliation(s)
- Bowen Liu
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qian Zhang
- Department of Biotherapy, Shenzhen Luohu People's Hospital, Shenzhen, China
| | - Chienchih Ke
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung City, Taiwan.,Biomedical Imaging Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Zhenyan Xia
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Cheng Luo
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Yang Li
- State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Xiaowei Guan
- Department of Human Anatomy and Histoembryology, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xiang Cao
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China
| | - Yun Xu
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Institute of Brain Science, Nanjing University, Nanjing, China
| | - Yonghua Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
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Varrault A, Journot L, Bouschet T. Cerebral Cortex Generated from Pluripotent Stem Cells to Model Corticogenesis and Rebuild Cortical Circuits: In Vitro Veritas? Stem Cells Dev 2019; 28:361-369. [PMID: 30661489 DOI: 10.1089/scd.2018.0233] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Organoids and cells generated in vitro from pluripotent stem cells (PSCs) are considered to be robust models of development and a conceivable source of transplants for putative cell therapy. However, a fundamental question about organoids and cells generated from PSCs is as follows: do they faithfully reproduce the in vivo tissue they are supposed to mimic and replace? This question is particularly relevant to complex tissues such as the cerebral cortex. In this review, we have tackled this issue by comparing cerebral cortices generated in vitro from PSCs to the in vivo cortex, with a particular focus on their respective cellular composition, molecular and epigenetic signatures, and brain connectivity. In short, in vitro cortex generated from PSCs reproduces most of the cardinal features of the in vivo cortex, including temporal corticogenesis and connectivity when PSC-derived cortical cells are grafted in recipient mouse cortex. However, compared to in vivo cortex, in vitro cortex lacks microglia and blood vessels and is less mature. Recent experiments show that the brain of the transplanted host provides these missing cell types together with an environment that promotes the synaptic maturation of the cortical transplant. Taken together, these data suggest that corticogenesis is largely intrinsic and well recapitulated in vitro, while the full maturation of cortical cells requires additional environmental clues. Finally, we propose some lines of work to improve corticogenesis from PSCs as a tool to model corticogenesis and rebuild cortical circuits.
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Affiliation(s)
- Annie Varrault
- Institut de Génomique Fonctionnelle, IGF, CNRS, INSERM, Université de Montpellier, Montpellier, France
| | - Laurent Journot
- Institut de Génomique Fonctionnelle, IGF, CNRS, INSERM, Université de Montpellier, Montpellier, France
| | - Tristan Bouschet
- Institut de Génomique Fonctionnelle, IGF, CNRS, INSERM, Université de Montpellier, Montpellier, France
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45
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Okado H. Regulation of brain development and brain function by the transcriptional repressor RP58. Brain Res 2019; 1705:15-23. [PMID: 29501651 DOI: 10.1016/j.brainres.2018.02.042] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 02/24/2018] [Accepted: 02/25/2018] [Indexed: 12/16/2022]
Abstract
The mechanisms regulating the formation of the cerebral cortex have been well studied. In the developing cortex, (also known Znf238, Zfp238, and Zbtb18), which encodes a sequence-specific transcriptional repressor, is expressed in glutamatergic projection neurons and progenitor cells. Targeted deletion of Rp58 leads to dysplasia of the neocortex and hippocampus, a reduction in the number of mature cortical neurons, and defects in laminar organization due to abnormal neuronal migration within the cortical plate. During late embryogenesis, Rp58-deficient mice have larger numbers of progenitor cells due to a delay in cell cycle exit. RP58 represses all four Id genes (Id1-Id4), which regulate cell cycle exit in the developing cerebral cortex, and is essential for transcriptional repression of Ngn2 and Rnd2, which regulate the multipolar-to-bipolar transition during neuronal migration independently of its role in cell cycle exit.
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Affiliation(s)
- Haruo Okado
- Tokyo Metropolitan Institute of Medical Science, Brain Development and Neural Degeneration, Neural Development Project, Japan.
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Feltrin AS, Tahira AC, Simões SN, Brentani H, Martins DC. Assessment of complementarity of WGCNA and NERI results for identification of modules associated to schizophrenia spectrum disorders. PLoS One 2019; 14:e0210431. [PMID: 30645614 PMCID: PMC6333352 DOI: 10.1371/journal.pone.0210431] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 12/21/2018] [Indexed: 02/07/2023] Open
Abstract
Psychiatric disorders involve both changes in multiple genes as well different types of variations. As such, gene co-expression networks allowed the comparison of different stages and parts of the brain contributing to an integrated view of genetic variation. Two methods based on co-expression networks presents appealing results: Weighted Gene Correlation Network Analysis (WGCNA) and Network-Medicine Relative Importance (NERI). By selecting two different gene expression databases related to schizophrenia, we evaluated the biological modules selected by both WGCNA and NERI along these databases as well combining both WGCNA and NERI results (WGCNA-NERI). Also we conducted a enrichment analysis for the identification of partial biological function of each result (as well a replication analysis). To appraise the accuracy of whether both algorithms (as well our approach, WGCNA-NERI) were pointing to genes related to schizophrenia and its complex genetic architecture we conducted the MSET analysis, based on a reference gene list of schizophrenia database (SZDB) related to DNA Methylation, Exome, GWAS as well as copy number variation mutation studies. The WGCNA results were more associated with inflammatory pathways and immune system response; NERI obtained genes related with cellular regulation, embryological pathways e cellular growth factors. Only NERI were able to provide a statistical meaningful results to the MSET analysis (for Methylation and de novo mutations data). However, combining WGCNA and NERI provided a much more larger overlap in these two categories and additionally on Transcriptome database. Our study suggests that using both methods in combination is better for establishing a group of modules and pathways related to a complex disease than using each method individually. NERI is available at: https://bitbucket.org/sergionery/neri.
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Affiliation(s)
- Arthur Sant’Anna Feltrin
- Center for Mathematics, Computation and Cognition, Federal University of ABC (UFABC), Santo André, SP, Brazil
- * E-mail: (ASF); (DCMJ)
| | - Ana Carolina Tahira
- LIM23, Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Sérgio Nery Simões
- Federal Institute of Education, Science and Technology of Espírito Santo, Serra, ES, Brazil
| | - Helena Brentani
- LIM23, Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
- Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
- National Institute of Developmental Psychiatry for Children and Adolescents (INPD), São Paulo, SP, Brazil
| | - David Corrêa Martins
- Center for Mathematics, Computation and Cognition, Federal University of ABC (UFABC), Santo André, SP, Brazil
- * E-mail: (ASF); (DCMJ)
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Dixit AB, Sharma D, Tripathi M, Srivastava A, Paul D, Prakash D, Sarkar C, Kumar K, Banerjee J, Chandra PS. Genome-wide DNA Methylation and RNAseq Analyses Identify Aberrant Signalling Pathways in Focal Cortical Dysplasia (FCD) Type II. Sci Rep 2018; 8:17976. [PMID: 30568293 PMCID: PMC6299275 DOI: 10.1038/s41598-018-35892-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 10/01/2018] [Indexed: 01/26/2023] Open
Abstract
Focal cortical dysplasia (FCD) is one of the most common pathologies associated with drug-resistant epilepsy (DRE). The pharmacological targets remain obscured, as the molecular mechanisms underlying FCD are unclear. Implications of epigenetically modulated aberrant gene expression in disease progression are reported in various DRE pathologies except FCD. Here we performed genome-wide CpG-DNA methylation profiling by methylated DNA immunoprecipitation (MeDIP) microarray and RNA sequencing (RNAseq) on cortical tissues resected from FCD type II patients. A total of 19088 sites showed altered DNA methylation in all the CpG islands. Of these, 5725 sites were present in the promoter regions, of which 176 genes showed an inverse correlation between methylation and gene expression. Many of these 176 genes were found to belong to a cohesive network of physically interacting proteins linked to several cellular functions. Pathway analysis revealed significant enrichment of receptor tyrosine kinases (RTK), EGFR, PDGFRA, NTRK3, and mTOR signalling pathways. This is the first study that investigates the epigenetic signature associated with FCD type II pathology. The candidate genes and pathways identified in this study may play a crucial role in the regulation of the pathogenic mechanisms of epileptogenesis associated with FCD type II pathologies.
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Affiliation(s)
- Aparna Banerjee Dixit
- Center of Excellence for Epilepsy, A joint NBRC-AIIMS collaboration, NBRC, Manesar, India. .,Dr. B R Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
| | - Devina Sharma
- Center of Excellence for Epilepsy, A joint NBRC-AIIMS collaboration, NBRC, Manesar, India.,Department of Neurosurgery, AIIMS, New Delhi, India
| | - Manjari Tripathi
- Center of Excellence for Epilepsy, A joint NBRC-AIIMS collaboration, NBRC, Manesar, India.,Department of Neurology, AIIMS, New Delhi, India
| | | | - Debasmita Paul
- Center of Excellence for Epilepsy, A joint NBRC-AIIMS collaboration, NBRC, Manesar, India.,Department of Neurosurgery, AIIMS, New Delhi, India
| | - Deepak Prakash
- Department of Forensic Medicine and Toxicology, AIIMS, New Delhi, India
| | | | - Krishan Kumar
- Center of Excellence for Epilepsy, A joint NBRC-AIIMS collaboration, NBRC, Manesar, India.,Department of Neurosurgery, AIIMS, New Delhi, India
| | - Jyotirmoy Banerjee
- Center of Excellence for Epilepsy, A joint NBRC-AIIMS collaboration, NBRC, Manesar, India.,Department of Biophysics, AIIMS, New Delhi, India
| | - P Sarat Chandra
- Center of Excellence for Epilepsy, A joint NBRC-AIIMS collaboration, NBRC, Manesar, India. .,Department of Neurosurgery, AIIMS, New Delhi, India.
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Hadar A, Milanesi E, Walczak M, Puzianowska-Kuźnicka M, Kuźnicki J, Squassina A, Niola P, Chillotti C, Attems J, Gozes I, Gurwitz D. SIRT1, miR-132 and miR-212 link human longevity to Alzheimer's Disease. Sci Rep 2018; 8:8465. [PMID: 29855513 PMCID: PMC5981646 DOI: 10.1038/s41598-018-26547-6] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 05/15/2018] [Indexed: 01/13/2023] Open
Abstract
Alzheimer's Disease (AD) is the most common cause of dementia in the elderly. Centenarians - reaching the age of >100 years while maintaining good cognitive skills - seemingly have unique biological features allowing healthy aging and protection from dementia. Here, we studied the expression of SIRT1 along with miR-132 and miR-212, two microRNAs known to regulate SIRT1, in lymphoblastoid cell lines (LCLs) from 45 healthy donors aged 21 to 105 years and 24 AD patients, and in postmortem olfactory bulb and hippocampus tissues from 14 AD patients and 20 age-matched non-demented individuals. We observed 4.0-fold (P = 0.001) lower expression of SIRT1, and correspondingly higher expression of miR-132 (1.7-fold; P = 0.014) and miR-212 (2.1-fold; P = 0.036), in LCLs from AD patients compared with age-matched healthy controls. Additionally, SIRT1 expression was 2.2-fold (P = 0.001) higher in centenarian LCLs compared with LCLs from individuals aged 56-82 years; while centenarian LCLs miR-132 and miR-212 indicated 7.6-fold and 4.1-fold lower expression, respectively. Correlations of SIRT1, miR-132 and miR-212 expression with cognitive scores were observed for AD patient-derived LCLs and postmortem AD olfactory bulb and hippocampus tissues, suggesting that higher SIRT1 expression, possibly mediated by lower miR-132 and miR-212, may protect aged individuals from dementia and is reflected in their peripheral tissues.
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Affiliation(s)
- A Hadar
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel
| | - E Milanesi
- Department of Cellular and Molecular Medicine, Victor Babes National Institute of Pathology, Bucharest, Romania
| | - M Walczak
- Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Warsaw, Poland
| | - M Puzianowska-Kuźnicka
- Department of Human Epigenetics, Mossakowski Medical Research Centre, Warsaw, Poland
- Department of Geriatrics and Gerontology, Medical Centre of Postgraduate Education, Warsaw, Poland
| | - J Kuźnicki
- The International Institute of Molecular and Cell Biology, Warsaw, Poland
| | - A Squassina
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - P Niola
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - C Chillotti
- Unit of Clinical Pharmacology, University Hospital of Cagliari, Cagliari, Italy
| | - J Attems
- Institute of Neuroscience and Newcastle University Institute of Ageing, Newcastle University, Newcastle upon Tyne, UK
| | - I Gozes
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
- Adams Super Center for Brain Studies, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
| | - D Gurwitz
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
- Adams Super Center for Brain Studies, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
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Human-Specific NOTCH2NL Genes Expand Cortical Neurogenesis through Delta/Notch Regulation. Cell 2018; 173:1370-1384.e16. [PMID: 29856955 PMCID: PMC6092419 DOI: 10.1016/j.cell.2018.03.067] [Citation(s) in RCA: 281] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 02/16/2018] [Accepted: 03/26/2018] [Indexed: 12/03/2022]
Abstract
The cerebral cortex underwent rapid expansion and increased complexity during recent hominid evolution. Gene duplications constitute a major evolutionary force, but their impact on human brain development remains unclear. Using tailored RNA sequencing (RNA-seq), we profiled the spatial and temporal expression of hominid-specific duplicated (HS) genes in the human fetal cortex and identified a repertoire of 35 HS genes displaying robust and dynamic patterns during cortical neurogenesis. Among them NOTCH2NL, human-specific paralogs of the NOTCH2 receptor, stood out for their ability to promote cortical progenitor maintenance. NOTCH2NL promote the clonal expansion of human cortical progenitors, ultimately leading to higher neuronal output. At the molecular level, NOTCH2NL function by activating the Notch pathway through inhibition of cis Delta/Notch interactions. Our study uncovers a large repertoire of recently evolved genes active during human corticogenesis and reveals how human-specific NOTCH paralogs may have contributed to the expansion of the human cortex.
Identification of >35 HS protein-coding genes expressed during human corticogenesis NOTCH2NL human-specific paralogs of NOTCH2 expressed in human cortical progenitors NOTCH2NL genes expand human cortical progenitors and their neuronal output NOTCH2NL promotes Notch signaling through cis-inhibition of Delta/Notch interactions
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Liu X, Ren S, Ge C, Cheng K, Li X, Zhao RC. Sca1+Lin−CD117− Mouse Bone Marrow-Derived Mesenchymal Stem Cells Regulate Immature Dendritic Cell Maturation by Inhibiting TLR4-IRF8 Signaling Via the Notch-RBP-J Pathway. Stem Cells Dev 2018; 27:556-565. [DOI: 10.1089/scd.2017.0235] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Xingxia Liu
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Shaoda Ren
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing, People's Republic of China
- Central Laboratory, Liaocheng People's Hospital, Liaocheng, People's Republic of China
| | - Chaozhuo Ge
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Kai Cheng
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Xiaojing Li
- School of Pharmacy, Liaocheng University, Liaocheng, People's Republic of China
| | - Robert Chunhua Zhao
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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