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Dai D, Sari EM, Si J, Ashari H, Dagong MIA, Pauciullo A, Lenstra JA, Han J, Zhang Y. Genomic analysis reveals the association of KIT and MITF variants with the white spotting in swamp buffaloes. BMC Genomics 2024; 25:713. [PMID: 39048931 PMCID: PMC11267946 DOI: 10.1186/s12864-024-10634-2] [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: 02/24/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Swamp-type buffaloes with varying degrees of white spotting are found exclusively in Tana Toraja, South Sulawesi, Indonesia, where spotted buffalo bulls are highly valued in accordance with the Torajan customs. The white spotting depigmentation is caused by the absence of melanocytes. However, the genetic variants that cause this phenotype have not been fully characterized. The objective of this study was to identify the genomic regions and variants responsible for this unique coat-color pattern. RESULTS Genome-wide association study (GWAS) and selection signature analysis identified MITF as a key gene based on the whole-genome sequencing data of 28 solid and 39 spotted buffaloes, while KIT was also found to be involved in the development of this phenotype by a candidate gene approach. Alternative candidate mutations included, in addition to the previously reported nonsense mutation c.649 C > T (p.Arg217*) and splice donor mutation c.1179 + 2T > A in MITF, a nonsense mutation c.2028T > A (p.Tyr676*) in KIT. All these three mutations were located in the genomic regions that were highly conserved exclusively in Indonesian swamp buffaloes and they accounted largely (95%) for the manifestation of white spotting. Last but not the least, ADAMTS20 and TWIST2 may also contribute to the diversification of this coat-color pattern. CONCLUSIONS The alternative mutations identified in this study affect, at least partially and independently, the development of melanocytes. The presence and persistence of such mutations may be explained by significant financial and social value of spotted buffaloes used in historical Rambu Solo ceremony in Tana Toraja, Indonesia. Several de novo spontaneous mutations have therefore been favored by traditional breeding for the spotted buffaloes.
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Affiliation(s)
- Dongmei Dai
- State Key Laboratory of Animal Biotech Breeding, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Eka Meutia Sari
- Department of Animal Science, Agriculture Faculty, Universitas Syiah Kuala (USK), Banda Aceh, 23111, Indonesia.
| | - Jingfang Si
- State Key Laboratory of Animal Biotech Breeding, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Hidayat Ashari
- Research Center for Biosystematics and Evolution, National Research and Innovation Agency (BRIN), Cibinong, 16911, Indonesia
| | - Muhammad Ihsan Andi Dagong
- Animal Production Department, Faculty of Animal Science, Hasanuddin University, Makassar, 90245, Indonesia
| | - Alfredo Pauciullo
- Department of Agricultural, Forest and Food Sciences, University of Turin, Grugliasco (TO), 10095, Italy
| | - Johannes A Lenstra
- Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM, Utrecht, The Netherlands
| | - Jianlin Han
- Yazhouwan National Laboratory, Sanya, 572024, China
| | - Yi Zhang
- State Key Laboratory of Animal Biotech Breeding, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
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2
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Yu Y, Yu M, Luo L, Zhang Z, Zeng H, Chen Y, Lin Z, Chen M, Wang W. Molecular characteristics and immune microenvironment of gastrointestinal stromal tumours: targets for therapeutic strategies. Front Oncol 2024; 14:1405727. [PMID: 39070147 PMCID: PMC11272528 DOI: 10.3389/fonc.2024.1405727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 06/24/2024] [Indexed: 07/30/2024] Open
Abstract
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours, arising mainly from the interstitial cells of Cajal (ICCs) of the gastrointestinal tract. As radiotherapy and chemotherapy are generally ineffective for GISTs, the current primary treatment is surgical resection. However, surgical resection is not choice for most patients. Therefore, new therapeutic strategies are urgently needed. Targeted therapy, represented by tyrosine kinase inhibitors (TKIs), and immunotherapy, represented by immune checkpoint inhibitor therapies and chimeric antigen receptor T-cell immunotherapy (CAR-T), offer new therapeutic options in GISTs and have shown promising treatment responses. In this review, we summarize the molecular classification and immune microenvironment of GISTs and discuss the corresponding targeted therapy and immunotherapy options. This updated knowledge may provide more options for future therapeutic strategies and applications in GISTs.
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Affiliation(s)
- Yang Yu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Mengdie Yu
- Guangzhou KingMed Diagnostics Group Co., Ltd., Guangzhou, Guangdong, China
| | - Lijie Luo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Zijing Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Haiping Zeng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Yan Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Zeyu Lin
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Mengnan Chen
- Department of Thyroid and Breast Surgery, Baiyun Hospital, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Wei Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
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Kabirova E, Ryzhkova A, Lukyanchikova V, Khabarova A, Korablev A, Shnaider T, Nuriddinov M, Belokopytova P, Smirnov A, Khotskin NV, Kontsevaya G, Serova I, Battulin N. TAD border deletion at the Kit locus causes tissue-specific ectopic activation of a neighboring gene. Nat Commun 2024; 15:4521. [PMID: 38806452 PMCID: PMC11133455 DOI: 10.1038/s41467-024-48523-7] [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: 01/16/2023] [Accepted: 04/30/2024] [Indexed: 05/30/2024] Open
Abstract
Topologically associated domains (TADs) restrict promoter-enhancer interactions, thereby maintaining the spatiotemporal pattern of gene activity. However, rearrangements of the TADs boundaries do not always lead to significant changes in the activity pattern. Here, we investigated the consequences of the TAD boundaries deletion on the expression of developmentally important genes encoding tyrosine kinase receptors: Kit, Kdr, Pdgfra. We used genome editing in mice to delete the TADs boundaries at the Kit locus and characterized chromatin folding and gene expression in pure cultures of fibroblasts, mast cells, and melanocytes. We found that although Kit is highly active in both mast cells and melanocytes, deletion of the TAD boundary between the Kit and Kdr genes results in ectopic activation only in melanocytes. Thus, the epigenetic landscape, namely the mutual arrangement of enhancers and actively transcribing genes, is important for predicting the consequences of the TAD boundaries removal. We also found that mice without a TAD border between the Kit and Kdr genes have a phenotypic manifestation of the mutation - a lighter coloration. Thus, the data obtained shed light on the principles of interaction between the 3D chromatin organization and epigenetic marks in the regulation of gene activity.
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Affiliation(s)
- Evelyn Kabirova
- Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | | | | | - Anna Khabarova
- Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Alexey Korablev
- Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | | | | | - Polina Belokopytova
- Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
- Novosibirsk State University, Novosibirsk, Russia
| | | | | | | | - Irina Serova
- Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
| | - Nariman Battulin
- Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
- Novosibirsk State University, Novosibirsk, Russia.
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4
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Nagano H, Ohyama S, Sato A, Igarashi J, Yamamoto T, Kadoya M, Kobayashi M. Jejunal gastrointestinal stromal tumor that developed in a patient with neurofibromatosis type 1: a case report. Diagn Pathol 2023; 18:110. [PMID: 37789344 PMCID: PMC10546696 DOI: 10.1186/s13000-023-01398-6] [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: 08/14/2023] [Accepted: 09/28/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND Neurofibromatosis type 1 (NF1) is known to be associated with the frequent occurrence of unique gastrointestinal stromal tumors (GISTs), preferably occurring in the small intestine, with no mutations in the c-kit proto-oncogene or platelet-derived growth factor receptor-alpha (PDGFRA), with a high tendency for multifocal development, indolent nature, with low proliferation activity and favorable prognosis. CASE PRESENTATION A woman in her forties visited her local doctor complaining of menstrual pain; a large mass was detected in her lower abdomen, and she was referred to our hospital. The patient had hundreds of skin warts and café au lait spots. The patient's mother had been diagnosed with type 1 neurofibromatosis. The patient met the diagnostic criteria for NF1 and was diagnosed with NF1. Ultrasonography showed a large heterogeneous cystic mass with various echo patterns, solid compartments and multiple septations. Magnetic resonance imaging showed a multilocular cystic mass with liquid content exhibiting various intensities, including that of blood. A small round solid mass was also observed close to the cystic tumor. Contrast-enhanced computed tomography showed that the round solid mass showed strong enhancement in the early phase, unlike the cystic tumor component. Open laparotomy revealed a multicystic exophytic tumor measuring 11.5 cm originating from the jejunal wall, 20 cm distal to the duodenojejunal flexure. A solid tumor measuring 2.1 cm was also found on the anal side of the large tumor. We resected the short segment of the jejunum, including the two lesions. Microscopic findings revealed that the cystic and solid tumors consisted of spindle-shaped tumor cells showing little atypia with a fascicular or bundle arrangement. Nuclear mitosis was scarce. Immunostaining of the tumor cells showed positive staining for KIT and DOG1 and negative staining for S100 and desmin. The NF1 patient was diagnosed with multiple GISTs accompanied by intratumoral hemorrhagic denaturation arising from the jejunum. The TNM staging was pT4N0M0, stage IIIA. CONCLUSION We report a case of GISTs associated with NF1 that showed a jejunal origin, multifocal development and few mitotic figures. The recurrence risk, survival prognosis and need for adjuvant chemotherapy, particularly in cases where the initial GIST exhibits a very indolent pathology in NF1-related GISTs, remain to be elucidated.
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Affiliation(s)
- Hideki Nagano
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan.
| | - Shigekazu Ohyama
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Atsushi Sato
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Jun Igarashi
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Tomoko Yamamoto
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Masumi Kadoya
- Department of Radiology, Marunouchi Hospital, Matsumoto Nagano, Japan
| | - Mikiko Kobayashi
- Department of Pathology, Marunouchi Hospital, Matsumoto Nagano, Japan
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5
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Zhang F, Wang C, Xu H, Xia X, Luo X, Li K, Han J, Lei C, Chen N, Yue X. Genomic analysis reveals a KIT-related chromosomal translocation associated with the white coat phenotype in yak. J Anim Breed Genet 2023; 140:330-342. [PMID: 36789788 DOI: 10.1111/jbg.12761] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 01/25/2023] [Indexed: 02/16/2023]
Abstract
White coat pigmentation is a striking phenotype of many domesticated species and has various genetic controls. The Tianzhu White yak, an indigenous breed with a complete white coat, has fascinated Tibetans for centuries. However, the genetic basis of this trait remains unknown. Here, we conducted population genomics analysis and genome-wide association study based on the whole-genome sequencing data of 38 white and 59 non-white-coated yak. The results revealed the presence of KIT-linked Cs alleles characterized by the translocations between chromosomes 6 and 29 in all-white yak. Furthermore, structural variations showed additional duplications of the Cs alleles in white yak compared with colour-sidedness cattle. Interestingly, the Cs alleles associated with the white coat phenotype in yak were found to have introgressed from taurine cattle. Our findings unveil the shared genetic control of the white coat phenotype and its evolution in closely related bovine species.
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Affiliation(s)
- Fengwei Zhang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, China.,Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Chong Wang
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, China
| | - Haiyue Xu
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, China
| | - Xiaoting Xia
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Xiaoyu Luo
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Kaihui Li
- Extending Station for Animal Husbandry and Veterinary Technology of Tianzhu Tibetan Autonomous County, Tianzhu, China
| | - Jianlin Han
- CAAS-ILRI Joint Laboratory on Livestock and Forage Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Chuzhao Lei
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Ningbo Chen
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Xiangpeng Yue
- State Key Laboratory of Herbage Improvement and Grassland Agro-ecosystems, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, China
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6
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Healing the Broken Hearts: A Glimpse on Next Generation Therapeutics. HEARTS 2022. [DOI: 10.3390/hearts3040013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Cardiovascular diseases are the leading cause of death worldwide, accounting for 32% of deaths globally and thus representing almost 18 million people according to WHO. Myocardial infarction, the most prevalent adult cardiovascular pathology, affects over half a million people in the USA according to the last records of the AHA. However, not only adult cardiovascular diseases are the most frequent diseases in adulthood, but congenital heart diseases also affect 0.8–1.2% of all births, accounting for mild developmental defects such as atrial septal defects to life-threatening pathologies such as tetralogy of Fallot or permanent common trunk that, if not surgically corrected in early postnatal days, they are incompatible with life. Therefore, both congenital and adult cardiovascular diseases represent an enormous social and economic burden that invariably demands continuous efforts to understand the causes of such cardiovascular defects and develop innovative strategies to correct and/or palliate them. In the next paragraphs, we aim to briefly account for our current understanding of the cellular bases of both congenital and adult cardiovascular diseases, providing a perspective of the plausible lines of action that might eventually result in increasing our understanding of cardiovascular diseases. This analysis will come out with the building blocks for designing novel and innovative therapeutic approaches to healing the broken hearts.
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7
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Li H, Chen H, Zhang X, Qi Y, Wang B, Cui Y, Ren J, Zhao Y, Chen Y, Zhu T, Wang Y, Yao L, Guo Y, Zhu H, Li Y, Situ C, Guo X. Global phosphoproteomic analysis identified key kinases regulating male meiosis in mouse. Cell Mol Life Sci 2022; 79:467. [PMID: 35930080 PMCID: PMC11071816 DOI: 10.1007/s00018-022-04507-8] [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: 05/07/2022] [Revised: 07/20/2022] [Accepted: 07/25/2022] [Indexed: 11/03/2022]
Abstract
Meiosis, a highly conserved process in organisms from fungi to mammals, is subjected to protein phosphorylation regulation. Due to the low abundance of phosphorylation, there is a lack of systemic characterization of phosphorylation regulation of meiosis in mammals. Using the phosphoproteomic approach, we profiled large-scale phosphoproteome of purified primary spermatocytes undergoing meiosis I, and identified 14,660 phosphorylation sites in 4419 phosphoproteins. Kinase-substrate phosphorylation network analysis followed by in vitro meiosis study showed that CDK9 was essential for meiosis progression to metaphase I and had enriched substrate phosphorylation sites in proteins involved in meiotic cell cycle. In addition, histones and epigenetic factors were found to be widely phosphorylated. Among those, HASPIN was found to be essential for male fertility. Haspin knockout led to misalignment of chromosomes, apoptosis of metaphase spermatocytes and a decreased number of sperm by deregulation of H3T3ph, chromosomal passenger complex (CPC) and spindle assembly checkpoint (SAC). The complicated protein phosphorylation and its important regulatory functions in meiosis indicated that in-depth studies of phosphorylation-mediated signaling could help us elucidate the mechanisms of meiosis.
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Affiliation(s)
- Haojie Li
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Hong Chen
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Xiangzheng Zhang
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Yaling Qi
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Bing Wang
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Yiqiang Cui
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Jie Ren
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Yichen Zhao
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Yu Chen
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Tianyu Zhu
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Yue Wang
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Liping Yao
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Yueshuai Guo
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Hui Zhu
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China
| | - Yan Li
- Department of Clinical Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, China.
| | - Chenghao Situ
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China.
| | - Xuejiang Guo
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, 211166, China.
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Tsai M, Valent P, Galli SJ. KIT as a master regulator of the mast cell lineage. J Allergy Clin Immunol 2022; 149:1845-1854. [PMID: 35469840 PMCID: PMC9177781 DOI: 10.1016/j.jaci.2022.04.012] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/14/2022] [Accepted: 04/15/2022] [Indexed: 10/18/2022]
Abstract
The discovery in 1987/1988 and 1990 of the cell surface receptor KIT and its ligand, stem cell factor (SCF), was a critical achievement in efforts to understand the development and function of multiple distinct cell lineages. These include hematopoietic progenitors, melanocytes, germ cells, and mast cells, which all are significantly affected by loss-of-function mutations of KIT or SCF. Such mutations also influence the development and/or function of additional cells, including those in parts of the central nervous system and the interstitial cells of Cajal (which control gut motility). Many other cells can express KIT constitutively or during immune responses, including dendritic cells, eosinophils, type 2 innate lymphoid cells, and taste cells. Yet the biological importance of KIT in many of these cell types largely remains to be determined. We here review the history of work investigating mice with mutations affecting the white spotting locus (which encodes KIT) or the steel locus (which encodes SCF), focusing especially on the influence of such mutations on mast cells. We also briefly review efforts to target the KIT/SCF pathway with anti-SCF or anti-Kit antibodies in mouse models of allergic disorders, parasite immunity, or fibrosis in which mast cells are thought to play significant roles.
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Affiliation(s)
- Mindy Tsai
- Department of Pathology and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif
| | - Peter Valent
- Department of Internal Medicine I, Division of Hematology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria
| | - Stephen J Galli
- Department of Pathology and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, Calif; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, Calif.
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9
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Zhao R, Trainor PA. Epithelial to mesenchymal transition during mammalian neural crest cell delamination. Semin Cell Dev Biol 2022; 138:54-67. [PMID: 35277330 DOI: 10.1016/j.semcdb.2022.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 02/08/2022] [Accepted: 02/21/2022] [Indexed: 11/18/2022]
Abstract
Epithelial to mesenchymal transition (EMT) is a well-defined cellular process that was discovered in chicken embryos and described as "epithelial to mesenchymal transformation" [1]. During EMT, epithelial cells lose their epithelial features and acquire mesenchymal character with migratory potential. EMT has subsequently been shown to be essential for both developmental and pathological processes including embryo morphogenesis, wound healing, tissue fibrosis and cancer [2]. During the past 5 years, interest and study of EMT especially in cancer biology have increased exponentially due to the implied role of EMT in multiple aspects of malignancy such as cell invasion, survival, stemness, metastasis, therapeutic resistance and tumor heterogeneity [3]. Since the process of EMT in embryogenesis and cancer progression shares similar phenotypic changes, core transcription factors and molecular mechanisms, it has been proposed that the initiation and development of carcinoma could be attributed to abnormal activation of EMT factors usually required for normal embryo development. Therefore, developmental EMT mechanisms, whose timing, location, and tissue origin are strictly regulated, could prove useful for uncovering new insights into the phenotypic changes and corresponding gene regulatory control of EMT under pathological conditions. In this review, we initially provide an overview of the phenotypic and molecular mechanisms involved in EMT and discuss the newly emerging concept of epithelial to mesenchymal plasticity (EMP). Then we focus on our current knowledge of a classic developmental EMT event, neural crest cell (NCC) delamination, highlighting key differences in our understanding of NCC EMT between mammalian and non-mammalian species. Lastly, we highlight available tools and future directions to advance our understanding of mammalian NCC EMT.
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Affiliation(s)
- Ruonan Zhao
- Stowers Institute for Medical Research, Kansas City, MO, USA; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Paul A Trainor
- Stowers Institute for Medical Research, Kansas City, MO, USA; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
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10
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Capel B. Beatrice Mintz (1921-2022): an innovator in embryo research and cancer biology. Development 2022. [DOI: 10.1242/dev.200607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Blanche Capel
- Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
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11
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Nishino S, Sakai N, Nishino N, Ono T. Brain Mast Cells in Sleep and Behavioral Regulation. Curr Top Behav Neurosci 2022; 59:427-446. [PMID: 35711025 DOI: 10.1007/7854_2022_359] [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] [Indexed: 06/15/2023]
Abstract
The function of mast cells in the brain for the mediation of neurobehavior is largely unknown. Mast cells are a heterogeneous population of granulocytic cells in the immune system. Mast cells contain numerous mediators, such as histamine, serotonin, cytokines, chemokines, and lipid-derived factors. Mast cells localize not only in the periphery but are also resident in the brain of mammalians. Mast cells in the brain are constitutively active, releasing their contents gradually or rapidly by anaphylactic degranulation. Their activity is also increased by a wide range of stimuli including both immune and non-immune signals. Brain mast cell neuromodulation may thus be involved in various neurobehavior in health and diseases.Using Kit mutant mast cell deficient mice (KitW/KitW-v), we obtained results indicating that brain mast cells regulate sleep/wake and other behavioral phenotypes and that histamine from brain mast cells promotes wakefulness. These findings were also confirmed using a newer inducible and Kit-independent mast cell deficient Mas-TRECK (toxin receptor knockout) mouse. Injections of diphtheria toxin (DT) selectively deplete mast cells and reduce wakefulness during the periods of mast cell depletion.We recently introduced a mouse model for chronic sleep loss associated with diabetes. The mice reared on the wire net for 3 weeks (i.e., mild stress [MS]) showed decreased amount of non-rapid eye movement (NREM) sleep, increased sleep fragmentation, and abnormal glucose tolerance test [GTT] and insulin tolerance test [ITT], phenotypes which mirror human chronic insomnia. Interestingly, these mice with insomnia showed an increased number of mast cells in both the brain and adipose tissue. Mast cell deficient mice (KitW/KitW-v) and inhibition of mast cell functions with cromolyn or a histamine H1 receptor antagonist administration ameliorated both insomnia and abnormal glycometabolism. Mast cells may therefore represent an important pathophysiological mediator in sleep impairments and abnormal glycometabolism associated with chronic insomnia.
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Affiliation(s)
- Seiji Nishino
- Sleep and Circadian Neurobiology Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA.
| | - Noriaki Sakai
- Sleep and Circadian Neurobiology Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Naoya Nishino
- Sleep and Circadian Neurobiology Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Taisuke Ono
- Sleep and Circadian Neurobiology Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA
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12
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Acar S, Armstrong AE, Hirbe AC. Plexiform neurofibroma: shedding light on the investigational agents in clinical trials. Expert Opin Investig Drugs 2021; 31:31-40. [PMID: 34932916 DOI: 10.1080/13543784.2022.2022120] [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: 10/19/2022]
Abstract
INTRODUCTION Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic condition, which predisposes individuals to the development of plexiform neurofibromas (PN), benign nerve sheath tumors seen in 30-50% of patients with NF1. These tumors may cause significant pain and disfigurement or may compromise organ function. Given the morbidity associated with these tumors, therapeutic options for patients with NF1-related PN are necessary. AREAS COVERED We searched the www.clinicaltrials.gov database for 'plexiform neurofibroma.' This article summarizes completed and ongoing trials involving systemic therapies for PN. EXPERT OPINION Surgery is the mainstay treatment; however, complete resection is not possible in many cases. Numerous systemic therapies have been evaluated in patients with NF1, with MEK inhibitors (MEKi) showing the greatest efficacy for volumetric reduction and improvement in functional and patient-reported outcomes. The MEKi selumetinib is now FDA approved for the treatment of inoperable, symptomatic PN in pediatric NF1 patients. Questions remain regarding the use of this drug class in terms of when to initiate therapy, overall duration, reduced dosing schedules, and side effect management. Future studies are needed to fully understand the clinical application of MEKi and to evaluate other potential therapies through appropriate trial designs for this potentially devastating, manifestation in NF1.
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Affiliation(s)
- Simge Acar
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.,School of Medicine, Koç University, Istanbul, Turkey
| | - Amy E Armstrong
- Division of Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, Mo, USA.,Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Angela C Hirbe
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.,Division of Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, Mo, USA.,Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
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13
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Differentiation of fetal hematopoietic stem cells requires ARID4B to restrict autocrine KITLG/KIT-Src signaling. Cell Rep 2021; 37:110036. [PMID: 34818550 PMCID: PMC8722094 DOI: 10.1016/j.celrep.2021.110036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 07/15/2021] [Accepted: 11/01/2021] [Indexed: 11/26/2022] Open
Abstract
Balance between the hematopoietic stem cell (HSC) duality to either possess self-renewal capacity or differentiate into multipotency progenitors (MPPs) is crucial for maintaining homeostasis of the hematopoietic stem/progenitor cell (HSPC) compartment. To retain the HSC self-renewal activity, KIT, a receptor tyrosine kinase, in HSCs is activated by its cognate ligand KITLG originating from niche cells. Here, we show that AT-rich interaction domain 4B (ARID4B) interferes with KITLG/KIT signaling, consequently allowing HSC differentiation. Conditional Arid4b knockout in mouse hematopoietic cells blocks fetal HSC differentiation, preventing hematopoiesis. Mechanistically, ARID4B-deficient HSCs self-express KITLG and overexpress KIT. As to downstream pathways of KITLG/KIT signaling, inhibition of Src family kinases rescues the HSC differentiation defect elicited by ARID4B loss. In summary, the intrinsic ARID4B-KITLG/KIT-Src axis is an HSPC regulatory program that enables the differentiation state, while KIT stimulation by KITLG from niche cells preserves the HSPC undifferentiated pool. Hematopoietic stem cells (HSCs) at the top of the hematopoietic hierarchy are able to self-renew and differentiate to mature blood cells. Young et al. report that an HSC self-control mechanism established by ARID4B ensures HSC differentiation. ARID4B-deficient HSCs produce KITLG to stimulate KIT, leading to blockage of HSC differentiation and eventual hematopoietic failure.
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14
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Burton JJN, Luke AJ, Pepling ME. Regulation of mouse primordial follicle formation by signaling through the PI3K pathway. Biol Reprod 2021; 106:515-525. [PMID: 34725674 DOI: 10.1093/biolre/ioab204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/04/2021] [Accepted: 10/27/2021] [Indexed: 11/13/2022] Open
Abstract
Cell signaling mediated by the KIT receptor is critical for many aspects of oogenesis including the proliferation and migration of primordial germ cells, as well as the survival, growth, and maturation of ovarian follicles. We previously showed that KIT regulates cyst breakdown and primordial follicle formation, and in this study, have investigated the mechanisms downstream of the receptor by modulating the activity of two downstream signaling cascades: the phosphoinositide 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) pathways. E17.5 ovaries were cultured for five days with a daily dose of media supplemented with either the PI3K inhibitor LY294002, the MEK inhibitor U0126, or a DMSO vehicle control. Our histological observations aligned with the established role of PI3K in oocyte growth and primordial follicle activation but also revealed that LY294002 treatment delayed the processes of cyst breakdown and primordial follicle formation. U0126 treatment also led to a reduction in oocyte growth and follicle development but did not appear to affect cyst breakdown. The delay in cyst breakdown was mitigated when ovaries were dually dosed with LY294002 and KITL, suggesting that while KIT may signal through PI3K to promote cyst breakdown, other signaling networks downstream of the receptor could compensate. These observations unearth a role for PI3K signaling in the establishment of the ovarian reserve and suggest that PI3K might be the primary mediator of KIT-induced cyst breakdown and primordial follicle formation in the mouse ovary.
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Affiliation(s)
| | - Amanda J Luke
- Department of Biology, Syracuse University, Syracuse, New York
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15
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Pathania S, Pentikäinen OT, Singh PK. A holistic view on c-Kit in cancer: Structure, signaling, pathophysiology and its inhibitors. Biochim Biophys Acta Rev Cancer 2021; 1876:188631. [PMID: 34606974 DOI: 10.1016/j.bbcan.2021.188631] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/08/2021] [Accepted: 09/28/2021] [Indexed: 11/18/2022]
Abstract
Receptor tyrosine kinases play an important role in many cellular processes, and their dysregulation leads to diseases, most importantly cancer. One such receptor tyrosine kinase is c-Kit, a type-III receptor tyrosine kinase, which is involved in various intracellular signaling pathways. The role of different mutant isoforms of c-Kit has been established in several types of cancers. Accordingly, promising c-Kit inhibition results have been reported for the treatment of different cancers (e.g., gastrointestinal stromal tumors, melanoma, acute myeloid leukemia, and other tumors). Therefore, lots of effort has been put to target c-Kit for the treatment of cancer. Here, we provide a comprehensive compilation to provide an insight into c-Kit inhibitor discovery. This compilation provides key information regarding the structure, signaling pathways related to c-Kit, and, more importantly, pharmacophores, binding modes, and SAR analysis for almost all small-molecule heterocycles reported for their c-Kit inhibitory activity. This work could be used as a guide in understanding the basic requirements for targeting c-Kit, and how the selectivity and efficacy of the molecules have been achieved till today.
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Affiliation(s)
- Shelly Pathania
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ghal Kalan, Ferozpur G.T. Road, Moga 142001, Punjab, India
| | - Olli T Pentikäinen
- Integrative Physiology and Pharmacology, Institute of Biomedicine, Faculty of Medicine, University of Turku, FI-20520 Turku, Finland
| | - Pankaj Kumar Singh
- Integrative Physiology and Pharmacology, Institute of Biomedicine, Faculty of Medicine, University of Turku, FI-20520 Turku, Finland.
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16
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Kihara T, Yuan J, Watabe T, Kitajima K, Kimura N, Ohkouchi M, Hashikura Y, Ohkubo S, Takahashi T, Hirota S. Pimitespib is effective on cecal GIST in a mouse model of familial GISTs with KIT-Asp820Tyr mutation through KIT signaling inhibition. Exp Mol Pathol 2021; 123:104692. [PMID: 34606780 DOI: 10.1016/j.yexmp.2021.104692] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/10/2021] [Accepted: 09/28/2021] [Indexed: 01/01/2023]
Abstract
Three families with multiple gastrointestinal stromal tumors (GISTs) caused by a germline Asp820Tyr mutation at exon 17 of the c-kit gene (KIT-Asp820Tyr) have been reported. We previously generated a knock-in mouse model of the family, and the mice with KIT-Asp818Tyr corresponding to human KIT-Asp820Tyr showed a cecal tumor equivalent to human GIST. In the model mice, we reported that tyrosine kinase inhibitor, imatinib, could stabilize but not decrease the cecal tumor volume. In this report, we examined whether a heat shock protein 90 inhibitor, pimitespib (TAS-116), has an inhibitory effect on phosphorylation of KIT-Asp818Tyr and can decrease the cecal tumor volume in the model mice. First, we showed that pimitespib inhibited KIT phosphorylation both dose- and time-dependently in KIT-Asp818Tyr transfected murine Ba/F3 cells. Then, four 1-week courses of pimitespib were orally administered to heterozygous (KIT-Asp818Tyr/+) model mice. Each course consisted of once-daily administration for consecutive 5 days followed by 2 days-off. Cecal tumors were dissected, and tumor volume was histologically analyzed, Ki-67 labeling index was immunohistochemically examined, and apoptotic figures were counted. Compared to the vehicle treated mice, pimitespib administered mice showed statistically significantly smaller cecal tumor volume, lower Ki-67 labeling index, and higher number of apoptotic figures in 10 high power fields (P = 0.0344, P = 0.0019 and P = 0.0269, respectively). Western blotting revealed that activation of KIT signaling molecules was strongly inhibited in the tumor tissues of pimitespib-administered mice compared to control mice. Thus, pimitespib seemed to inhibit in vivo tumor progression effectively in the model mice. These results suggest that the progression of multiple GISTs in patients with germline KIT-Asp820Tyr might be controllable by pimitespib.
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Affiliation(s)
- Takako Kihara
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Jiayin Yuan
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tadashi Watabe
- Department of Radiology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazuhiro Kitajima
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Neinei Kimura
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Mizuka Ohkouchi
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yuka Hashikura
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shuichi Ohkubo
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd, Tsukuba, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan.
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17
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Ben Maamar M, Nilsson EE, Skinner MK. Epigenetic transgenerational inheritance, gametogenesis and germline development†. Biol Reprod 2021; 105:570-592. [PMID: 33929020 PMCID: PMC8444706 DOI: 10.1093/biolre/ioab085] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/12/2021] [Accepted: 04/22/2021] [Indexed: 12/14/2022] Open
Abstract
One of the most important developing cell types in any biological system is the gamete (sperm and egg). The transmission of phenotypes and optimally adapted physiology to subsequent generations is in large part controlled by gametogenesis. In contrast to genetics, the environment actively regulates epigenetics to impact the physiology and phenotype of cellular and biological systems. The integration of epigenetics and genetics is critical for all developmental biology systems at the cellular and organism level. The current review is focused on the role of epigenetics during gametogenesis for both the spermatogenesis system in the male and oogenesis system in the female. The developmental stages from the initial primordial germ cell through gametogenesis to the mature sperm and egg are presented. How environmental factors can influence the epigenetics of gametogenesis to impact the epigenetic transgenerational inheritance of phenotypic and physiological change in subsequent generations is reviewed.
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Affiliation(s)
- Millissia Ben Maamar
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, USA
| | - Eric E Nilsson
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, USA
| | - Michael K Skinner
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, USA
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18
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Saravanaperumal SA, Pallotti S, Pediconi D, Renieri C, La Terza A. Exon-1 skipping and intron-1 retaining by alternative splicing of the c-KIT gene encodes a novel splice variant in the skin of Merino sheep (Ovis aries). Mol Biol Rep 2021; 48:4987-4994. [PMID: 34148208 DOI: 10.1007/s11033-021-06486-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 06/08/2021] [Indexed: 12/01/2022]
Abstract
c-KIT, a type III receptor protein tyrosine kinase, plays an essential role in melanocyte development, migration, and survival. Mutations within the c-KIT gene are previously shown to cause the white coat color phenotypes in pigs, mice, goats, and humans. However, up so far, the splicing isoform(s), genomic architecture of c-KIT have not been characterized well in merino sheep. Reverse transcriptase (RT)-PCR analysis with molecular prediction identified two basic splice variants: Transcript Variant-1, 2 for 12 bp insertion coding sequences (CDS) corresponding to the four amino acids 'GNSK', respectively. Using 5' RACE, here we report for the first time a novel c-KIT 'Transcript Variant-3' from the skin of merino sheep by comparative genome analyses at exon(1)-intron(1)-exon(2) boundaries. In contrast, a single product of 795 bp was characterized by 3' RACE. We also demonstrated that the c-KIT gene expression at the transcript level is not mediated via an intron-9 splicing event. Overall, beyond what was observed in other mammals, our data provide novel insights into the molecular structure of the c-KIT gene in sheep.
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Affiliation(s)
- Siva Arumugam Saravanaperumal
- Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First Street SW Guggenheim 10-21C, Rochester, MN, 55905, USA.
| | - Stefano Pallotti
- School of Pharmacy, University of Camerino, Via Gentile III da Varano, 62032, Camerino, Italy.
| | - Dario Pediconi
- School of Pharmacy, University of Camerino, Via Gentile III da Varano, 62032, Camerino, Italy
| | - Carlo Renieri
- School of Pharmacy, University of Camerino, Via Gentile III da Varano, 62032, Camerino, Italy
| | - Antonietta La Terza
- School of Biosciences and Veterinary Medicine, University of Camerino, Via Gentile III da Varano, 62032, Camerino, Italy.
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19
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Xie M, Zhang S, Dong F, Zhang Q, Wang J, Wang C, Zhu C, Zhang S, Luo B, Wu P, Ema H. Granulocyte colony-stimulating factor directly acts on mouse lymphoid-biased but not myeloid-biased hematopoietic stem cells. Haematologica 2021; 106:1647-1658. [PMID: 32079694 PMCID: PMC8168498 DOI: 10.3324/haematol.2019.239251] [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: 09/26/2019] [Indexed: 11/30/2022] Open
Abstract
Granulocyte colony-stimulating factor (G-CSF) is widely used in clinical settings to mobilize hematopoietic stem cells (HSC) into the circulation for HSC harvesting and transplantation. However, whether G-CSF directly stimulates HSC to change their cell cycle state and fate is controversial. HSC are a heterogeneous population consisting of different types of HSC, such as myeloid-biased HSC and lymphoid-biased HSC. We hypothesized that G-CSF has different effects on different types of HSC. To verify this, we performed serum-free single-cell culture and competitive repopulation with cultured cells. Single highly purified HSC and hematopoietic progenitor cells (HPC) were cultured with stem cell factor (SCF), SCF + G-CSF, SCF + granulocyte/macrophage (GM)-CSF, or SCF + thrombopoietin (TPO) for 7 days. Compared with SCF alone, SCF + G-CSF increased the number of divisions of cells from the lymphoid-biased HSCenriched population but not that of cells from the My-bi HSC-enriched population. SCF + G-CSF enhanced the level of reconstitution of lymphoidbiased HSC but not that of myeloid-biased HSC. Clonal transplantation assay also showed that SCF + G-CSF did not increase the frequency of myeloid-biased HSC. These data showed that G-CSF directly acted on lymphoid- biased HSC but not myeloid-biased HSC. Our study also revised the cytokine network at early stages of hematopoiesis: SCF directly acted on myeloid-biased HSC; TPO directly acted on myeloid-biased HSC and lymphoid- biased HSC; and GM-CSF acted only on HPC. Early hematopoiesis is controlled differentially and sequentially by a number of cytokines.
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Affiliation(s)
- Miner Xie
- Institute of Hematology and Blood Diseases Hospital
| | | | - Fang Dong
- Institute of Hematology and Blood Diseases Hospital
| | | | - Jinhong Wang
- Institute of Hematology and Blood Diseases Hospital
| | | | - Caiying Zhu
- nstitute of Hematology and Blood Diseases Hospital
| | - Sen Zhang
- nstitute of Hematology and Blood Diseases Hospital
| | - Bingqing Luo
- nstitute of Hematology and Blood Diseases Hospital
| | - Peng Wu
- nstitute of Hematology and Blood Diseases Hospital
| | - Hideo Ema
- Institute of Hematology and Blood Diseases Hospital
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20
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Mollace V, Rosano GMC, Anker SD, Coats AJS, Seferovic P, Mollace R, Tavernese A, Gliozzi M, Musolino V, Carresi C, Maiuolo J, Macrì R, Bosco F, Chiocchi M, Romeo F, Metra M, Volterrani M. Pathophysiological Basis for Nutraceutical Supplementation in Heart Failure: A Comprehensive Review. Nutrients 2021; 13:257. [PMID: 33477388 PMCID: PMC7829856 DOI: 10.3390/nu13010257] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/25/2020] [Accepted: 01/13/2021] [Indexed: 02/06/2023] Open
Abstract
There is evidence demonstrating that heart failure (HF) occurs in 1-2% of the global population and is often accompanied by comorbidities which contribute to increasing the prevalence of the disease, the rate of hospitalization and the mortality. Although recent advances in both pharmacological and non-pharmacological approaches have led to a significant improvement in clinical outcomes in patients affected by HF, residual unmet needs remain, mostly related to the occurrence of poorly defined strategies in the early stages of myocardial dysfunction. Nutritional support in patients developing HF and nutraceutical supplementation have recently been shown to possibly contribute to protection of the failing myocardium, although their place in the treatment of HF requires further assessment, in order to find better therapeutic solutions. In this context, the Optimal Nutraceutical Supplementation in Heart Failure (ONUS-HF) working group aimed to assess the optimal nutraceutical approach to HF in the early phases of the disease, in order to counteract selected pathways that are imbalanced in the failing myocardium. In particular, we reviewed several of the most relevant pathophysiological and molecular changes occurring during the early stages of myocardial dysfunction. These include mitochondrial and sarcoplasmic reticulum stress, insufficient nitric oxide (NO) release, impaired cardiac stem cell mobilization and an imbalanced regulation of metalloproteinases. Moreover, we reviewed the potential of the nutraceutical supplementation of several natural products, such as coenzyme Q10 (CoQ10), a grape seed extract, Olea Europea L.-related antioxidants, a sodium-glucose cotransporter (SGLT2) inhibitor-rich apple extract and a bergamot polyphenolic fraction, in addition to their support in cardiomyocyte protection, in HF. Such an approach should contribute to optimising the use of nutraceuticals in HF, and the effect needs to be confirmed by means of more targeted clinical trials exploring the efficacy and safety of these compounds.
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Affiliation(s)
- Vincenzo Mollace
- Department of Health Sciences, Institute of Research for Food Safety & Health, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (R.M.); (A.T.); (M.G.); (V.M.); (C.C.); (J.M.); (R.M.); (F.B.)
| | - Giuseppe M. C. Rosano
- Cardiology Clinical Academic Group, St George’s Hospitals NHS Trust University of London, London SW17 0QT, UK;
- Department of Cardiology, IRCCS San Raffaele Pisana, 00166 Rome, Italy; (A.J.S.C.); (M.V.)
| | - Stefan D. Anker
- Department of Cardiology, Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Andrew J. S. Coats
- Department of Cardiology, IRCCS San Raffaele Pisana, 00166 Rome, Italy; (A.J.S.C.); (M.V.)
| | - Petar Seferovic
- Faculty of Medicine, Belgrade University, 11000 Belgrade, Serbia;
| | - Rocco Mollace
- Department of Health Sciences, Institute of Research for Food Safety & Health, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (R.M.); (A.T.); (M.G.); (V.M.); (C.C.); (J.M.); (R.M.); (F.B.)
- Department of Experimental and Applied Medicine, Institute of Cardiology, University of Brescia, 25121 Brescia, Italy;
| | - Annamaria Tavernese
- Department of Health Sciences, Institute of Research for Food Safety & Health, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (R.M.); (A.T.); (M.G.); (V.M.); (C.C.); (J.M.); (R.M.); (F.B.)
- Department of Experimental and Applied Medicine, Institute of Cardiology, University of Brescia, 25121 Brescia, Italy;
| | - Micaela Gliozzi
- Department of Health Sciences, Institute of Research for Food Safety & Health, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (R.M.); (A.T.); (M.G.); (V.M.); (C.C.); (J.M.); (R.M.); (F.B.)
| | - Vincenzo Musolino
- Department of Health Sciences, Institute of Research for Food Safety & Health, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (R.M.); (A.T.); (M.G.); (V.M.); (C.C.); (J.M.); (R.M.); (F.B.)
| | - Cristina Carresi
- Department of Health Sciences, Institute of Research for Food Safety & Health, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (R.M.); (A.T.); (M.G.); (V.M.); (C.C.); (J.M.); (R.M.); (F.B.)
| | - Jessica Maiuolo
- Department of Health Sciences, Institute of Research for Food Safety & Health, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (R.M.); (A.T.); (M.G.); (V.M.); (C.C.); (J.M.); (R.M.); (F.B.)
| | - Roberta Macrì
- Department of Health Sciences, Institute of Research for Food Safety & Health, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (R.M.); (A.T.); (M.G.); (V.M.); (C.C.); (J.M.); (R.M.); (F.B.)
| | - Francesca Bosco
- Department of Health Sciences, Institute of Research for Food Safety & Health, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (R.M.); (A.T.); (M.G.); (V.M.); (C.C.); (J.M.); (R.M.); (F.B.)
| | - Marcello Chiocchi
- Department of Diagnostic Imaging and Interventional Radiology, Policlinico Tor Vergata, 00199 Rome, Italy;
| | - Francesco Romeo
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00199 Rome, Italy;
| | - Marco Metra
- Department of Experimental and Applied Medicine, Institute of Cardiology, University of Brescia, 25121 Brescia, Italy;
| | - Maurizio Volterrani
- Department of Cardiology, IRCCS San Raffaele Pisana, 00166 Rome, Italy; (A.J.S.C.); (M.V.)
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21
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Zebrafish Kit ligands cooperate with erythropoietin to promote erythroid cell expansion. Blood Adv 2020; 4:5915-5924. [PMID: 33259600 DOI: 10.1182/bloodadvances.2020001700] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 10/20/2020] [Indexed: 01/09/2023] Open
Abstract
Kit ligand (Kitlg) is pleiotropic cytokine with a prominent role in vertebrate erythropoiesis. Although the role of Kitlg in this process has not been reported in Danio rerio (zebrafish), in the present study we show that its function is evolutionarily conserved. Zebrafish possess 2 copies of Kitlg genes (Kitlga and Kitlgb) as a result of whole-genome duplication. To determine the role of each ligand in zebrafish, we performed a series of ex vivo and in vivo gain- and loss-of-function experiments. First, we tested the biological activity of recombinant Kitlg proteins in suspension culture from zebrafish whole-kidney marrow, and we demonstrate that Kitlga is necessary for expansion of erythroid progenitors ex vivo. To further address the role of kitlga and kitlgb in hematopoietic development in vivo, we performed gain-of-function experiments in zebrafish embryos, showing that both ligands cooperate with erythropoietin (Epo) to promote erythroid cell expansion. Finally, using the kita mutant (kitab5/b5 or sparse), we show that the Kita receptor is crucial for Kitlga/b cooperation with Epo in erythroid cells. In summary, using optimized suspension culture conditions with recombinant cytokines (Epo, Kitlga), we report, for the first time, ex vivo suspension cultures of zebrafish hematopoietic progenitor cells that can serve as an indispensable tool to study normal and aberrant hematopoiesis in zebrafish. Furthermore, we conclude that, although partial functional diversification of Kit ligands has been described in other processes, in erythroid development, both paralogs play a similar role, and their function is evolutionarily conserved.
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22
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Kishi K, Kamizaki M, Kaji N, Iino S, Hori M. A Close Relationship Between Networks of Interstitial Cells of Cajal and Gastrointestinal Transit In Vivo. Front Pharmacol 2020; 11:587453. [PMID: 33633564 PMCID: PMC7902082 DOI: 10.3389/fphar.2020.587453] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 10/14/2020] [Indexed: 01/02/2023] Open
Abstract
The interstitial cells of Cajal associated with the myenteric plexus (ICC-MP) are located in the same area as the myenteric plexus. ICC-MP networks are linked to the generation of electrical pacemaker activity that causes spontaneous gastrointestinal (GI) contractions; however, its role in GI transit is not clear. The aim of this study was to comprehensively investigate the effect of ICC-MP disruption on GI transit in vivo using W/Wv mice, partially ICC-deficient model mice. In this study, we measured GI transit using a 13C-octanoic acid breath test, an orally administered dye and a bead expulsion assay. ICC were detected by immunohistochemical staining for c-Kit, a specific marker for ICC. Interestingly, we found that gastric emptying in W/Wv mice was normal. We also found that the ability of small intestinal and colonic transit was significantly reduced in W/Wv mice. Immunohistochemical staining using whole-mount muscularis samples revealed that c-Kit-positive ICC-MP networks were formed in wild-type mice. In contrast, ICC-MP networks in W/Wv mice were maintained only in the gastric antrum and were significantly reduced in the ileum and colon. No significant changes were observed in the nerve structures of the myenteric plexus in W/Wv mice. These findings suggest that ICC-MP contribute to GI transit as a powerful driving function in vivo.
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Affiliation(s)
- Kazuhisa Kishi
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Moe Kamizaki
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Noriyuki Kaji
- Department of Pharmacology, School of Veterinary Medicine, Azabu University, Kanagawa, Japan
| | - Satoshi Iino
- Division of Anatomy and Neuroscience, Department of Morphological and Physiological Sciences, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Masatoshi Hori
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
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23
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Iino S, Horiguchi S, Horiguchi K, Hashimoto T. Interstitial cells of Cajal in W sh/W sh c-kit mutant mice. J Smooth Muscle Res 2020; 56:58-68. [PMID: 33132281 PMCID: PMC7596356 DOI: 10.1540/jsmr.56.58] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The c-Kit receptor tyrosine kinase regulates the development and differentiation of
several progenitor cells. In the gastrointestinal (GI) tract, the c-Kit regulates the
development of the interstitial cells of Cajal (ICC) that are responsible for motility
regulation of the GI musculature. W-sash
(Wsh) is an inversion mutation upstream of the
c-kit promoter region that affects a key regulatory element, resulting
in cell-type-specific altered gene expression, leading to a decrease in the number of mast
cells, melanocytes, and ICC. We extensively examined the GI tract of
Wsh/Wsh mice using
immunohistochemistry and electron microscopy. Although the musculature of the
Wsh/Wsh mice did not show any
c-Kit immunoreactivity, we detected intensive immunoreactivity for transmembrane member
16A (TMEM16A, anoctamin-1), another ICC marker. TMEM16A immunopositive cells were observed
as ICC-MY in the gastric corpus-antrum and the large intestine, ICC-DMP in the small
intestine, and ICC-SM in the colon. Electron microscopic analysis revealed these cells as
ICC from their ultrastructural features, such as numerous mitochondria and caveolae, and
their close contact with nerve terminals. In the developmental period, we examined 14.5
and 18.5 day embryos but did not observe c-Kit immunoreactivity in the
Wsh/Wsh small intestine. From
this study, ICC subtypes developed and maturated structurally without c-Kit expression.
Wsh/Wsh mice are a new model
to investigate the effects of c-Kit and unknown signaling on ICC development and
function.
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Affiliation(s)
- Satoshi Iino
- Department of Anatomy, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui 910-1193, Japan
| | - Satomi Horiguchi
- Department of Anatomy, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui 910-1193, Japan
| | - Kazuhide Horiguchi
- Department of Anatomy, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui 910-1193, Japan
| | - Takashi Hashimoto
- Department of Anatomy, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui 910-1193, Japan
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24
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Ramaswamy A, Chaudhari V, Bhargava P, Bhandare M, Kumar R, Shrikhande SV, Ostwal V. Gastrointestinal Stromal Tumor – An Overview. Indian J Med Paediatr Oncol 2020. [DOI: 10.4103/ijmpo.ijmpo_45_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
AbstractGastrointestinal stromal tumors (GISTs) are rare tumors but are most common mesenchymal tumors of the digestive tract. They are commonly seen in the stomach (60%) and small intestine (30%). GISTs are likely derived from the interstitial cells of Cajal or their stem cell precursors. They are best characterized by computerized tomography and have a specific staining pattern on immunohistochemistry, i.e., C-Kit and DOG-1. The treatment of GIST is based on the risk assessment for relapse, and patients with localized GIST require resection with or without adjuvant imatinib mesylate (IM). Advanced unresectable tumors are usually treated with IM, with a number of further options available for patients post progression on IM. There is an increasing emphasis on identifying C-Kit and platelet-derived growth factor receptor alpha mutations in all patients with GIST, as these are driver mutations with current and future therapeutic implications.
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Affiliation(s)
- Anant Ramaswamy
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Vikram Chaudhari
- GI and HPB Surgery, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Prabhat Bhargava
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Manish Bhandare
- GI and HPB Surgery, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Rajiv Kumar
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Shailesh v Shrikhande
- GI and HPB Surgery, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Vikas Ostwal
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
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25
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Xie Y, Wei BH, Ni FD, Yang WX. Conversion from spermatogonia to spermatocytes: Extracellular cues and downstream transcription network. Gene 2020; 764:145080. [PMID: 32858178 DOI: 10.1016/j.gene.2020.145080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 08/16/2020] [Accepted: 08/19/2020] [Indexed: 12/15/2022]
Abstract
Spermatocyte (spc) formation from spermatogonia (spg) differentiation is the first step of spermatogenesis which produces prodigious spermatozoa for a lifetime. After decades of studies, several factors involved in the functioning of a mouse were discovered both inside and outside spg. Considering the peculiar expression and working pattern of each factor, this review divides the whole conversion of spg to spc into four consecutive development processes with a focus on extracellular cues and downstream transcription network in each one. Potential coordination among Dmrt1, Sohlh1/2 and BMP families mediates Ngn3 upregulation, which marks progenitor spg, with other changes. After that, retinoic acid (RA), as a master regulator, promotes A1 spg formation with its helpers and Sall4. A1-to-B spg transition is under the control of Kitl and impulsive RA signaling together with early and late transcription factors Stra8 and Dmrt6. Finally, RA and its responsive effectors conduct the entry into meiosis. The systematic transcription network from outside to inside still needs research to supplement or settle the controversials in each process. As a step further ahead, this review provides possible drug targets for infertility therapy by cross-linking humans and mouse model.
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Affiliation(s)
- Yi Xie
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Bang-Hong Wei
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Fei-Da Ni
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wan-Xi Yang
- The Sperm Laboratory, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
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26
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Persistent Human KIT Receptor Signaling Disposes Murine Placenta to Premature Differentiation Resulting in Severely Disrupted Placental Structure and Functionality. Int J Mol Sci 2020; 21:ijms21155503. [PMID: 32752102 PMCID: PMC7432075 DOI: 10.3390/ijms21155503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/28/2020] [Accepted: 07/30/2020] [Indexed: 12/12/2022] Open
Abstract
Activating mutations in the human KIT receptor is known to drive severe hematopoietic disorders and tumor formation spanning various entities. The most common mutation is the substitution of aspartic acid at position 816 to valine (D816V), rendering the receptor constitutively active independent of ligand binding. As the role of the KIT receptor in placental signaling cascades is poorly understood, we analyzed the impact of KITD816V expression on placental development using a humanized mouse model. Placentas from KITD816V animals present with a grossly changed morphology, displaying a reduction in labyrinth and spongiotrophoblast layer and an increase in the Parietal Trophoblast Giant Cell (P-TGC) layer. Elevated differentiation to P-TGCs was accompanied with reduced differentiation to other Trophoblast Giant Cell (TGC) subtypes and by severe decrease in proliferation. The embryos display growth retardation and die in utero. KITD816V-trophoblast stem cells (TSC) differentiate much faster compared to wild type (WT) controls. In undifferentiated KITD816V-TSCs, levels of Phosphorylated Extracellular-signal Regulated Kinase (P-ERK) and Phosphorylated Protein Kinase B (P-AKT) are comparable to wildtype cultures differentiating for 3–6 days. Accordingly, P-TGC markers Placental Lactogen 1 (PL1) and Proliferin (PLF) are upregulated as well. The results reveal that KIT signaling orchestrates the fine-tuned differentiation of the placenta, with special emphasis on P-TGC differentiation. Appropriate control of KIT receptor action is therefore essential for placental development and nourishment of the embryo.
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27
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Wang YB, de Lartigue G, Page AJ. Dissecting the Role of Subtypes of Gastrointestinal Vagal Afferents. Front Physiol 2020; 11:643. [PMID: 32595525 PMCID: PMC7300233 DOI: 10.3389/fphys.2020.00643] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/20/2020] [Indexed: 12/22/2022] Open
Abstract
Gastrointestinal (GI) vagal afferents convey sensory signals from the GI tract to the brain. Numerous subtypes of GI vagal afferent have been identified but their individual roles in gut function and feeding regulation are unclear. In the past decade, technical approaches to selectively target vagal afferent subtypes and to assess their function has significantly progressed. This review examines the classification of GI vagal afferent subtypes and discusses the current available techniques to study vagal afferents. Investigating the distribution of GI vagal afferent subtypes and understanding how to access and modulate individual populations are essential to dissect their fundamental roles in the gut-brain axis.
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Affiliation(s)
- Yoko B Wang
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Guillaume de Lartigue
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States.,Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, United States
| | - Amanda J Page
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Nutrition, Diabetes and Gut Health, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
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28
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On-Target CRISPR/Cas9 Activity Can Cause Undesigned Large Deletion in Mouse Zygotes. Int J Mol Sci 2020; 21:ijms21103604. [PMID: 32443745 PMCID: PMC7279260 DOI: 10.3390/ijms21103604] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/15/2020] [Accepted: 05/19/2020] [Indexed: 02/07/2023] Open
Abstract
Genome engineering has been tremendously affected by the appearance of the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-based approach. Initially discovered as an adaptive immune system for prokaryotes, the method has rapidly evolved over the last decade, overtaking multiple technical challenges and scientific tasks and becoming one of the most effective, reliable, and easy-to-use technologies for precise genomic manipulations. Despite its undoubtable advantages, CRISPR/Cas9 technology cannot ensure absolute accuracy and predictability of genomic editing results. One of the major concerns, especially for clinical applications, is mutations resulting from error-prone repairs of CRISPR/Cas9-induced double-strand DNA breaks. In some cases, such error-prone repairs can cause unpredicted and unplanned large genomic modifications within the CRISPR/Cas9 on-target site. Here we describe the largest, to the best of our knowledge, undesigned on-target deletion with a size of ~293 kb that occurred after the cytoplasmic injection of CRISPR/Cas9 system components into mouse zygotes and speculate about its origin. We suppose that deletion occurred as a result of the truncation of one of the ends of a double-strand break during the repair.
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29
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Galli SJ, Metz M, Starkl P, Marichal T, Tsai M. Mast cells and IgE in defense against lethality of venoms: Possible "benefit" of allergy[]. ALLERGO JOURNAL INTERNATIONAL 2020; 29:46-62. [PMID: 33224714 PMCID: PMC7673288 DOI: 10.1007/s40629-020-00118-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 10/20/2019] [Indexed: 01/15/2023]
Abstract
Physicians think of mast cells and IgE primarily in the context of allergic disorders, including fatal anaphylaxis. This 'bad side' of mast cells and IgE is so well accepted that it can be difficult to think of them in other contexts, particularly those in which they may have beneficial functions. However, there is evidence that mast cells and IgE, as well as basophils (circulating granulocytes whose functions partially overlap with those of mast cells), can contribute to host defense as components of adaptive type 2 immune responses to helminths, ticks and certain other parasites. Accordingly, allergies often are conceptualized as "misdirected" type 2 immune responses, in which IgE antibodies are produced against any of a diverse group of apparently harmless antigens, and against components of animal venoms. Indeed, certain unfortunate patients who have become sensitized to venoms develop severe IgE-associated allergic reactions, including fatal anaphylaxis, upon subsequent venom exposure. In this review, we will describe evidence that mast cells can enhance innate resistance, and survival, to challenge with reptile or arthropod venoms during a first exposure to such venoms. We also will discuss findings indicating that, in mice surviving an initial encounter with venom, acquired type 2 immune responses, IgE antibodies, the high affinity IgE receptor (FcεRI), and mast cells can contribute to acquired resistance to the lethal effects of both honeybee venom and Russell's viper venom. These findings support the hypothesis that mast cells and IgE can help protect the host against venoms and perhaps other noxious substances.
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Affiliation(s)
- Stephen J. Galli
- Department of Pathology and the Sean N. Parker Center for Allergy Research, Stanford University School of Medicine, Stanford, California, 94305; USA
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, 94305; USA
| | - Martin Metz
- Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Philipp Starkl
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
- Department of Medicine 1, Laboratory of Infection Biology, Medical University of Vienna, 1090 Vienna, Austria
| | - Thomas Marichal
- GIGA-Research and Faculty of Veterinary Medicine, University of Liege, 4000 Liege, Belgium
| | - Mindy Tsai
- Department of Pathology and the Sean N. Parker Center for Allergy Research, Stanford University School of Medicine, Stanford, California, 94305; USA
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30
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Galli SJ, Metz M, Starkl P, Marichal T, Tsai M. Mast cells and IgE in defense against lethality of venoms: Possible "benefit" of allergy*. ALLERGO JOURNAL 2020. [DOI: 10.1007/s15007-020-0746-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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31
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Sethumadhavan A, Mani M. Kit activates interleukin-4 receptor and effector signal transducer and activator of transcription 6 independent of its cognate ligand in mouse mast cells. Immunology 2020; 159:441-449. [PMID: 31957000 DOI: 10.1111/imm.13174] [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: 07/27/2019] [Revised: 12/01/2019] [Accepted: 12/17/2019] [Indexed: 11/30/2022] Open
Abstract
Signaling by Kit has been extensively studied in hematopoietic cells and is essential for the survival, proliferation and maintenance of hematopoietic stem and progenitor cells. In addition to the activation of intrinsic signaling pathways, Kit has been shown to interact with lineage-restricted type I cytokine receptors and produce cross signals, e.g. erythropoietin receptor, interleukin-7 receptor (IL-7R), IL-3R. Based on the earlier studies, we hypothesize that Kit activate other type I cytokine receptors in a cell-specific manner and execute cell-specific function. To investigate other Kit-activated receptors, we tested Kit and IL-4R cross-receptor activation in murine bone-marrow-derived mast cells, which express both Kit and IL-4R at the surface level. Kit upon activation by Kit ligand (KL), activated IL-4Rα, γC , and signal transducer and activator of transcription 6 independent of its cognate ligand IL-4. Though KL and IL-4 are individually mitogenic, combinations of KL and IL-4 synergistically promoted mast cell proliferation. Furthermore, inhibition of lipid raft formation by methyl-β-cyclodextrin resulted in loss of synergistic proliferation. Together the data suggest IL-4R as a novel Kit-activated receptor. Such cross-receptor activations are likely to be a universal mechanism of Kit signaling in hematopoiesis.
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Affiliation(s)
- Aiswarya Sethumadhavan
- Cell Signaling Laboratory, Department of Microbiology, School of Life Sciences, Pondicherry University, Puducherry, India
| | - Maheswaran Mani
- Cell Signaling Laboratory, Department of Microbiology, School of Life Sciences, Pondicherry University, Puducherry, India
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32
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Henkel J, Saif R, Jagannathan V, Schmocker C, Zeindler F, Bangerter E, Herren U, Posantzis D, Bulut Z, Ammann P, Drögemüller C, Flury C, Leeb T. Selection signatures in goats reveal copy number variants underlying breed-defining coat color phenotypes. PLoS Genet 2019; 15:e1008536. [PMID: 31841508 PMCID: PMC6936872 DOI: 10.1371/journal.pgen.1008536] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 12/30/2019] [Accepted: 11/23/2019] [Indexed: 12/16/2022] Open
Abstract
Domestication and human selection have formed diverse goat breeds with characteristic phenotypes. This process correlated with the fixation of causative genetic variants controlling breed-specific traits within regions of reduced genetic diversity, so called selection signatures or selective sweeps. Using whole genome sequencing of DNA pools (pool-seq) from 20 genetically diverse modern goat breeds and bezoars, we identified 2,239 putative selection signatures. In two Pakistani goat breeds, Pak Angora and Barbari, we found selection signatures in a region harboring KIT, a gene involved in melanoblast development, migration, and survival. The search for candidate causative variants responsible for these selective sweeps revealed two different copy number variants (CNVs) downstream of KIT that were exclusively present in white Pak Angora and white-spotted Barbari goats. Several Swiss goat breeds selected for specific coat colors showed selection signatures at the ASIP locus encoding the agouti signaling protein. Analysis of these selective sweeps revealed four different CNVs associated with the white or tan (AWt), Swiss markings (Asm), badgerface (Ab), and the newly proposed peacock (Apc) allele. RNA-seq analyses on skin samples from goats with the different CNV alleles suggest that the identified structural variants lead to an altered expression of ASIP between eumelanistic and pheomelanistic body areas. Our study yields novel insights into the genetic control of pigmentation by identifying six functionally relevant CNVs. It illustrates how structural changes of the genome have contributed to phenotypic evolution in domestic goats. Domestic animals have been selected for hundreds or sometimes even thousands of years for traits that were appreciated by their human owners. This process correlated with the fixation of causative genetic variants controlling breed-specific traits within regions of reduced genetic diversity, so called selection signatures or selective sweeps. We conducted a comprehensive screen for selection signatures in 20 phenotypically and genetically diverse modern goat breeds and identified a total of 2,239 putative selection signatures in our dataset. Follow-up experiments on selection signatures harboring known candidate genes for coat color revealed six different copy number variants (CNVs). Two of these CNVs were located in the 3’-flanking region of KIT and associated with a completely white coat color phenotype in Pak Angora goats and a white-spotted coat color phenotype in Barbari goats, respectively. The other four CNVs were located at the ASIP locus. They were associated with four different types of coat color patterning in seven Swiss goat breeds. Their functional effect is mediated by region-specific quantitative changes in ASIP mRNA expression. Our study illustrates how structural changes of the genome have contributed to phenotypic evolution in domestic goats.
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Affiliation(s)
- Jan Henkel
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- DermFocus, University of Bern, Bern, Switzerland
| | - Rashid Saif
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- Institute of Biotechnology, Gulab Devi Educational Complex, Lahore, Pakistan
| | - Vidhya Jagannathan
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- DermFocus, University of Bern, Bern, Switzerland
| | - Corinne Schmocker
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Flurina Zeindler
- School of Agricultural, Forest and Food Sciences, Bern University of Applied Sciences, Zollikofen, Switzerland
| | | | - Ursula Herren
- Swiss Goat Breeding Association, Zollikofen, Switzerland
| | | | - Zafer Bulut
- Department of Biochemistry, Faculty of Veterinary Medicine, Selcuk University, Konya, Turkey
| | | | - Cord Drögemüller
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- DermFocus, University of Bern, Bern, Switzerland
| | - Christine Flury
- School of Agricultural, Forest and Food Sciences, Bern University of Applied Sciences, Zollikofen, Switzerland
| | - Tosso Leeb
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- DermFocus, University of Bern, Bern, Switzerland
- * E-mail:
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33
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Iino S, Horiguchi K, Horiguchi S. c-Kit-stem cell factor signal-independent development of interstitial cells of Cajal in murine small intestine. Cell Tissue Res 2019; 379:121-129. [PMID: 31741038 DOI: 10.1007/s00441-019-03120-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 10/06/2019] [Indexed: 01/08/2023]
Abstract
c-Kit receptor tyrosine kinase and its ligand stem cell factor (SCF) play critical roles in regulating the development and proliferation of various cells, including the interstitial cells of Cajal (ICC) in the gastrointestinal tract. Many subtypes of ICC are known to be lacking in c-Kit-SCF-insufficient mice, such as W/Wv and Sl/Sld, whereas ICC-deep muscular plexus (DMP) in small intestine are not lacking. In this study, we examine ICC-DMP development in normal and c-Kit-SCF signal-insufficient mice. In normal mice, numerous ICC-DMP labeled with c-Kit and neurokinin 1 receptor (NK1R) antibodies were observed only in the duodenum on the day of birth, in the duodenum and the jejunum on postnatal day 4 and throughout the small intestine after postnatal day 6. In W mutant mice (W/Wv, Wv/Wv, W/W), ICC-DMP investigated using c-Kit and NK1R immunoreactivities were similar to that in normal mice. c-Kit ligand SCF-deficient mice (Sl/Sl) also showed almost identical ICC-DMP development and proliferation as normal mice. These results show that the development and proliferation of ICC-DMP occur in the postnatal period independent of c-Kit-SCF signaling.
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Affiliation(s)
- Satoshi Iino
- Department of Anatomy, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui, 910-1193, Japan.
| | - Kazuhide Horiguchi
- Department of Anatomy, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui, 910-1193, Japan
| | - Satomi Horiguchi
- Department of Anatomy, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui, 910-1193, Japan
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34
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Mast cells drive IgE-mediated disease but might be bystanders in many other inflammatory and neoplastic conditions. J Allergy Clin Immunol 2019; 144:S19-S30. [DOI: 10.1016/j.jaci.2019.07.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 06/11/2019] [Accepted: 07/08/2019] [Indexed: 01/05/2023]
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35
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Gomes SA, Hare JM, Rangel EB. Kidney-Derived c-Kit + Cells Possess Regenerative Potential. Stem Cells Transl Med 2019; 7:317-324. [PMID: 29575816 PMCID: PMC5866938 DOI: 10.1002/sctm.17-0232] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 12/15/2017] [Accepted: 01/14/2018] [Indexed: 12/27/2022] Open
Abstract
Kidney‐derived c‐Kit+ cells exhibit progenitor/stem cell properties in vitro (self‐renewal capacity, clonogenicity, and multipotentiality). These cells can regenerate epithelial tubular cells following ischemia‐reperfusion injury and accelerate foot processes effacement reversal in a model of acute proteinuria in rats. Several mechanisms are involved in kidney regeneration by kidney‐derived c‐Kit+ cells, including cell engraftment and differentiation into renal‐like structures, such as tubules, vessels, and podocytes. Moreover, paracrine mechanisms could also account for kidney regeneration, either by stimulating proliferation of surviving cells or modulating autophagy and podocyte cytoskeleton rearrangement through mTOR‐Raptor and ‐Rictor signaling, which ultimately lead to morphological and functional improvement. To gain insights into the functional properties of c‐Kit+ cells during kidney development, homeostasis, and disease, studies on lineage tracing using transgenic mice will unveil their fate. The results obtained from these studies will set the basis for establishing further investigation on the therapeutic potential of c‐Kit+ cells for treatment of kidney disease in preclinical and clinical studies. stemcellstranslationalmedicine2018;7:317–324
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Affiliation(s)
- Samirah A Gomes
- Laboratory of Cellular, Genetic, and Molecular Nephrology, Renal Division, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of Medicine, University of Miami, Miami, Florida, USA.,Department of Molecular and Cellular Pharmacology, Leonard M Miller School of Medicine, University of Miami, Miami, Florida, USA.,Division of Cardiology, Leonard M Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Erika B Rangel
- Instituto Israelita de Ensino e Pesquisa Albert Einstein, Hospital Israelita Albert Einstein, São Paulo, São Paulo, Brazil.,Division of Nephrology, Federal University of São Paulo, São Paulo, São Paulo, Brazil
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36
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Gude NA, Sussman MA. Cardiac regenerative therapy: Many paths to repair. Trends Cardiovasc Med 2019; 30:338-343. [PMID: 31515053 DOI: 10.1016/j.tcm.2019.08.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 08/14/2019] [Accepted: 08/29/2019] [Indexed: 12/17/2022]
Abstract
Cardiovascular disease remains the primary cause of death in the United States and in most nations worldwide, despite ongoing intensive efforts to promote cardiac health and treat heart failure. Replacing damaged myocardium represents perhaps the most promising treatment strategy, but also the most challenging given that the adult mammalian heart is notoriously resistant to endogenous repair. Cardiac regeneration following pathologic challenge would require proliferation of surviving tissue, expansion and differentiation of resident progenitors, or transdifferentiation of exogenously applied progenitor cells into functioning myocardium. Adult cardiomyocyte proliferation has been the focus of investigation for decades, recently enjoying a renaissance of interest as a therapeutic strategy for reversing cardiomyocyte loss due in large part to ongoing controversies and frustrations with myocardial cell therapy outcomes. The promise of cardiac cell therapy originated with reports of resident adult cardiac stem cells that could be isolated, expanded and reintroduced into damaged myocardium, producing beneficial effects in preclinical animal models. Despite modest functional improvements, Phase I clinical trials using autologous cardiac derived cells have proven safe and effective, setting the stage for an ongoing multi-center Phase II trial combining autologous cardiac stem cell types to enhance beneficial effects. This overview will examine the history of these two approaches for promoting cardiac repair and attempt to provide context for current and future directions in cardiac regenerative research.
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Affiliation(s)
- Natalie A Gude
- SDSU Heart Institute and Biology Department, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA
| | - Mark A Sussman
- SDSU Heart Institute and Biology Department, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA.
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Li X, Sun T, Wang X, Tang J, Liu Y. Restore natural fertility of Kit w/Kit wv mouse with nonobstructive azoospermia through gene editing on SSCs mediated by CRISPR-Cas9. Stem Cell Res Ther 2019; 10:271. [PMID: 31445521 PMCID: PMC6708192 DOI: 10.1186/s13287-019-1386-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 08/04/2019] [Accepted: 08/15/2019] [Indexed: 12/15/2022] Open
Abstract
Background Male infertility is a serious social problem in modern society. Nonobstructive azoospermia (NOA) caused by germ cell gene defects is an important reason for male infertility, but effective clinical treatment for this disease has not been established. Methods We choose Kitw/Kitwv mouse as a research model and try to develop a new treatment strategy and “cure” its infertility. Mutant spermatogonial stem cells (SSCs) were isolated from one single unilateral testis of a 14-day-old Kitw/Kitwv mouse and propagated in vitro. The C to T point mutation on Kitwv site of these SSCs was corrected through CRISPR-Cas9-mediated homology-directed repair (HDR) in vitro. Then, the repaired SSCs were screened out, proliferated, and transplanted into the remaining testis, and complete spermatogenesis was established in the recipient testis. Results Healthy offsprings with wild type Kit gene or Kitw mutation were obtained through natural mating 4 months after SSC transplantation. Conclusion In this study, we established an effective new treatment strategy for NOA caused by germ cell gene defects through a combination of SSC isolation, CRISPR-Cas9-mediated gene editing, and SSC transplantation, which brought hope for these NOA patients to restore their natural fertility.
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Affiliation(s)
- Xiaoyu Li
- Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China. .,State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Tiecheng Sun
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xiuxia Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Jixin Tang
- Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.,State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yixun Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
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Hamadah I, Chisti M, Haider M, Al Dosssari H, Alhumaidan R, Meyer BF, Wakil SM. A novel KIT mutation in a family with expanded syndrome of piebaldism. JAAD Case Rep 2019; 5:627-631. [PMID: 31341943 PMCID: PMC6630042 DOI: 10.1016/j.jdcr.2019.01.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Issam Hamadah
- Department of Dermatology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Muzamil Chisti
- Department of Dermatology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mansoor Haider
- Department of Dermatology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Haya Al Dosssari
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Rawan Alhumaidan
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Brian F Meyer
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Salma M Wakil
- Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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Jones M, Sergeant C, Richardson M, Groth D, Brooks S, Munyard K. A non-synonymous SNP in exon 3 of the KIT gene is responsible for the classic grey phenotype in alpacas (Vicugna pacos). Anim Genet 2019; 50:493-500. [PMID: 31297861 DOI: 10.1111/age.12814] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2019] [Indexed: 11/30/2022]
Abstract
The alpaca classic grey phenotype is of particular interest to the industry. Until now, there were only indirect data suggesting that the KIT gene was involved in the classic grey phenotype. All exons of KIT in three black and three classic silvergrey alpacas were sequenced. Five non-synonymous SNPs were observed. There was only one SNP found that was present only in the silvergrey alpacas, and this was also the only SNP predicted to be damaging. This variant results in a change of a glycine (Gly) to an arginine (Arg) at amino acid position 126 (c.376G>A), occurring in the second Ig-like domain of the extracellular domain of KIT. Basic protein modelling predicted that this variant is likely destabilising. Therefore, an additional 488 alpacas were genotyped for this SNP using the tetra-primer amplification refractory mutation system PCR (Tetra-primer ARMS-PCR). All classic grey alpacas were observed to be heterozygous, and 99.3% of non-grey dark base colour alpacas were found to be homozygous for the wildtype allele in this position. These results confirm that the classic grey phenotype in alpacas is the result of a c.376G>A (p.Gly126Arg) SNP in exon 3 of KIT. These data also support the hypothesis that the grey phenotype is autosomal dominant and that the mutation is most likely homozygous lethal.
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Affiliation(s)
- M Jones
- CHIRI Biosciences, School of Pharmacy and Biomedical Sciences, Curtin University, Perth, 6845, WA, Australia
| | - C Sergeant
- CHIRI Biosciences, School of Pharmacy and Biomedical Sciences, Curtin University, Perth, 6845, WA, Australia
| | - M Richardson
- Genomics Research and Discovery Facility, School of Life and Environmental Sciences, Deakin University, Geelong, 3220, Vic., Australia
| | - D Groth
- CHIRI Biosciences, School of Pharmacy and Biomedical Sciences, Curtin University, Perth, 6845, WA, Australia
| | - S Brooks
- Department of Animal Science, UF Genetics Institute, University of Florida, Gainesville, FL, 32610, USA
| | - K Munyard
- CHIRI Biosciences, School of Pharmacy and Biomedical Sciences, Curtin University, Perth, 6845, WA, Australia
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Qin K, Liang X, Sun G, Shi X, Wang M, Liu H, Chen Y, Liu X, He Z. Highly efficient correction of structural mutations of 450 kb KIT locus in kidney cells of Yorkshire pig by CRISPR/Cas9. BMC Mol Cell Biol 2019; 20:4. [PMID: 31041890 PMCID: PMC6446502 DOI: 10.1186/s12860-019-0184-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 03/11/2019] [Indexed: 11/23/2022] Open
Abstract
The white coat colour of Yorkshire and Landrace pig breeds is caused by the dominant white I allele of KIT, associated with 450-kb duplications and a splice mutation (G > A) at the first base in intron 17. To test whether genome editing can be employed to correct this structural mutation, and to investigate the role of KIT in the control of porcine coat colour, we designed sgRNAs targeting either intron 16 or intron 17 of KIT, and transfected Cas9/sgRNA co-expression plasmids into the kidney cells of Yorkshire pigs. The copy number of KIT was reduced by about 13%, suggesting the possibility of obtaining cells with corrected structural mutations of the KIT locus. Using single cell cloning, from 24 successfully expanded single cell clones derived from cells transfected with sgRNA targeting at intron 17, we obtained 3 clones with a single copy of KIT without the splice mutation. Taken together, the 12.5% (3/24) efficiency of correction of structural mutations of 450 kb fragments is highly efficient, providing a solid basis for the generation of genome edited Yorkshire pigs with a normal KIT locus. This provides an insight into the underlying genetic mechanisms of porcine coat colour.
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Affiliation(s)
- Ke Qin
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China
| | - Xinyu Liang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China
| | - Guanjie Sun
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China
| | - Xuan Shi
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China
| | - Min Wang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China
| | - Hongbo Liu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China
| | - Yaosheng Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China
| | - Xiaohong Liu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China
| | - Zuyong He
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China.
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Li J, Chen W, Wu S, Ma T, Jiang H, Zhang Q. Differential expression of MC1R gene in Liaoning Cashmere goats with different coat colors. Anim Biotechnol 2019; 30:273-278. [DOI: 10.1080/10495398.2018.1485681] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- JianPing Li
- College of Animal Science and Technology, Jilin Agricultural Science and Technology University, Jilin, China
| | - Wei Chen
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - SuFang Wu
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Tao Ma
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - HuaiZhi Jiang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - QiaoLing Zhang
- College of Veterinary Medicine, Jilin University, Changchun, China
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Larose H, Shami AN, Abbott H, Manske G, Lei L, Hammoud SS. Gametogenesis: A journey from inception to conception. Curr Top Dev Biol 2019; 132:257-310. [PMID: 30797511 PMCID: PMC7133493 DOI: 10.1016/bs.ctdb.2018.12.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Gametogenesis, the process of forming mature germ cells, is an integral part of both an individual's and a species' health and well-being. This chapter focuses on critical male and female genetic and epigenetic processes underlying normal gamete formation through their differentiation to fertilization. Finally, we explore how knowledge gained from this field has contributed to progress in areas with great clinical promise, such as in vitro gametogenesis.
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Affiliation(s)
- Hailey Larose
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States
| | | | - Haley Abbott
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Gabriel Manske
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Lei Lei
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Biomedical Engineering, University of Michigan Medical School, Ann Arbor, MI, United States.
| | - Saher Sue Hammoud
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, United States.
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43
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Marino F, Scalise M, Cianflone E, Mancuso T, Aquila I, Agosti V, Torella M, Paolino D, Mollace V, Nadal-Ginard B, Torella D. Role of c-Kit in Myocardial Regeneration and Aging. Front Endocrinol (Lausanne) 2019; 10:371. [PMID: 31275242 PMCID: PMC6593054 DOI: 10.3389/fendo.2019.00371] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/24/2019] [Indexed: 12/15/2022] Open
Abstract
c-Kit, a type III receptor tyrosine kinase (RTK), is involved in multiple intracellular signaling whereby it is mainly considered a stem cell factor receptor, which participates in vital functions of the mammalian body, including the human. Furthermore, c-kit is a necessary yet not sufficient marker to detect and isolate several types of tissue-specific adult stem cells. Accordingly, c-kit was initially used as a marker to identify and enrich for adult cardiac stem/progenitor cells (CSCs) that were proven to be clonogenic, self-renewing and multipotent, being able to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro as well as in vivo after myocardial injury. Afterwards it was demonstrated that c-kit expression labels a heterogenous cardiac cell population, which is mainly composed by endothelial cells while only a very small fraction represents CSCs. Furthermore, c-kit as a signaling molecule is expressed at different levels in this heterogenous c-kit labeled cardiac cell pool, whereby c-kit low expressers are enriched for CSCs while c-kit high expressers are endothelial and mast cells. This heterogeneity in cell composition and expression levels has been neglected in recent genetic fate map studies focusing on c-kit, which have claimed that c-kit identifies cells with robust endothelial differentiation potential but with minimal if not negligible myogenic commitment potential. However, modification of c-kit gene for Cre Recombinase expression in these Cre/Lox genetic fate map mouse models produced a detrimental c-kit haploinsufficiency that prevents efficient labeling of true CSCs on one hand while affecting the regenerative potential of these cells on the other. Interestingly, c-kit haploinsufficiency in c-kit-deficient mice causes a worsening myocardial repair after injury and accelerates cardiac aging. Therefore, these studies have further demonstrated that adult c-kit-labeled CSCs are robustly myogenic and that the adult myocardium relies on c-kit expression to regenerate after injury and to counteract aging effects on cardiac structure and function.
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Affiliation(s)
- Fabiola Marino
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
- Department of Health Sciences, Interregional Research Center on Food Safety and Health (IRC-FSH), University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Mariangela Scalise
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Eleonora Cianflone
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Teresa Mancuso
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Iolanda Aquila
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Valter Agosti
- Interdepartmental Center of Services (CIS) of Genomics, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Michele Torella
- Department of Cardiothoracic Sciences, University of Campania L. Vanvitelli, Naples, Italy
| | - Donatella Paolino
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Vincenzo Mollace
- Department of Health Sciences, Interregional Research Center on Food Safety and Health (IRC-FSH), University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Bernardo Nadal-Ginard
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
- StemCell OpCo, Madrid, Spain
| | - Daniele Torella
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
- *Correspondence: Daniele Torella
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Abstract
Humoral regulation by ligand/receptor interactions is a fundamental feature of vertebrate hematopoiesis. Zebrafish are an established vertebrate animal model of hematopoiesis, sharing with mammals conserved genetic, molecular and cell biological regulatory mechanisms. This comprehensive review considers zebrafish hematopoiesis from the perspective of the hematopoietic growth factors (HGFs), their receptors and their actions. Zebrafish possess multiple HGFs: CSF1 (M-CSF) and CSF3 (G-CSF), kit ligand (KL, SCF), erythropoietin (EPO), thrombopoietin (THPO/TPO), and the interleukins IL6, IL11, and IL34. Some ligands and/or receptor components have been duplicated by various mechanisms including the teleost whole genome duplication, adding complexity to the ligand/receptor interactions possible, but also providing examples of several different outcomes of ligand and receptor subfunctionalization or neofunctionalization. CSF2 (GM-CSF), IL3 and IL5 and their receptors are absent from zebrafish. Overall the humoral regulation of hematopoiesis in zebrafish displays considerable similarity with mammals, which can be applied in biological and disease modelling research.
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Affiliation(s)
- Vahid Pazhakh
- a Australian Regenerative Medicine Institute, Monash University , Clayton , Australia
| | - Graham J Lieschke
- a Australian Regenerative Medicine Institute, Monash University , Clayton , Australia
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45
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Dinsmore CJ, Soriano P. MAPK and PI3K signaling: At the crossroads of neural crest development. Dev Biol 2018; 444 Suppl 1:S79-S97. [PMID: 29453943 PMCID: PMC6092260 DOI: 10.1016/j.ydbio.2018.02.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 02/06/2018] [Accepted: 02/06/2018] [Indexed: 02/08/2023]
Abstract
Receptor tyrosine kinase-mediated growth factor signaling is essential for proper formation and development of the neural crest. The many ligands and receptors implicated in these processes signal through relatively few downstream pathways, frequently converging on the MAPK and PI3K pathways. Despite decades of study, there is still considerable uncertainty about where and when these signaling pathways are required and how they elicit particular responses. This review summarizes our current understanding of growth factor-induced MAPK and PI3K signaling in the neural crest.
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Affiliation(s)
- Colin J Dinsmore
- Department of Cell, Developmental and Regenerative Biology, Tisch Cancer Institute, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA
| | - Philippe Soriano
- Department of Cell, Developmental and Regenerative Biology, Tisch Cancer Institute, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA.
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46
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Chovanec M, Albany C, Mego M, Montironi R, Cimadamore A, Cheng L. Emerging Prognostic Biomarkers in Testicular Germ Cell Tumors: Looking Beyond Established Practice. Front Oncol 2018; 8:571. [PMID: 30547014 PMCID: PMC6280583 DOI: 10.3389/fonc.2018.00571] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 11/14/2018] [Indexed: 11/21/2022] Open
Abstract
Testicular germ cell tumors are unique among solid cancers. Historically, this disease was deadly if progressed beyond the stage I. The implementation of cisplatin-based chemotherapy regimens has drastically changed the clinical outcome of metastatic testicular cancer. Several biomarkers were established to refine the prognosis by International Germ Cell Collaborative Group in 1997. Among these, the most significant were primary tumor site; metastatic sites, such as non-pulmonary visceral metastases; and the amplitude of serum tumor markers α-fetoprotein, β-chorionic gonadotropin, and lactate dehydrogenase. Since then, oncology has experienced discoveries of various molecular biomarkers to further refine the prognosis and treatment of malignancies. However, the ability to predict the prognosis and treatment response in germ cell tumors did not improve for many years. Clinical trials with novel targeting agents that were conducted in refractory germ cell tumor patients have proven to have negative outcomes. With the recent advances and developments, novel biomarkers emerge in the field of germ cell tumor oncology. This review article aims to summarize the current knowledge in the research of novel prognostic biomarkers in testicular germ cell tumors.
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Affiliation(s)
- Michal Chovanec
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
- Division of Hematology and Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, United States
| | - Costantine Albany
- Division of Hematology and Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, United States
| | - Michal Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Rodolfo Montironi
- Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
| | - Alessia Cimadamore
- Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Urology, Indiana University School of Medicine, Indianapolis, IN, United States
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48
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Mehta C, Johnson KD, Gao X, Ong IM, Katsumura KR, McIver SC, Ranheim EA, Bresnick EH. Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program. Cell Rep 2018; 20:2966-2979. [PMID: 28930689 DOI: 10.1016/j.celrep.2017.08.090] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 07/30/2017] [Accepted: 08/25/2017] [Indexed: 12/20/2022] Open
Abstract
Hematopoietic development requires the transcription factor GATA-2, and GATA-2 mutations cause diverse pathologies, including leukemia. GATA-2-regulated enhancers increase Gata2 expression in hematopoietic stem/progenitor cells and control hematopoiesis. The +9.5-kb enhancer activates transcription in endothelium and hematopoietic stem cells (HSCs), and its deletion abrogates HSC generation. The -77-kb enhancer activates transcription in myeloid progenitors, and its deletion impairs differentiation. Since +9.5-/- embryos are HSC deficient, it was unclear whether the +9.5 functions in progenitors or if GATA-2 expression in progenitors solely requires -77. We further dissected the mechanisms using -77;+9.5 compound heterozygous (CH) mice. The embryonic lethal CH mutation depleted megakaryocyte-erythrocyte progenitors (MEPs). While the +9.5 suffices for HSC generation, the -77 and +9.5 must reside on one allele to induce MEPs. The -77 generated burst-forming unit-erythroid through the induction of GATA-1 and other GATA-2 targets. The enhancer circuits controlled signaling pathways that orchestrate a GATA factor-dependent blood development program.
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Affiliation(s)
- Charu Mehta
- UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Kirby D Johnson
- UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Xin Gao
- UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Irene M Ong
- UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI 53705, USA
| | - Koichi R Katsumura
- UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Skye C McIver
- UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Erik A Ranheim
- Department of Pathology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Emery H Bresnick
- UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
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Caslin HL, Kiwanuka KN, Haque TT, Taruselli MT, MacKnight HP, Paranjape A, Ryan JJ. Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today. Front Immunol 2018; 9:868. [PMID: 29755466 PMCID: PMC5932183 DOI: 10.3389/fimmu.2018.00868] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 04/09/2018] [Indexed: 01/13/2023] Open
Abstract
Mast cells are tissue resident, innate immune cells with heterogenous phenotypes tuned by cytokines and other microenvironmental stimuli. Playing a protective role in parasitic, bacterial, and viral infections, mast cells are also known for their role in the pathogenesis of allergy, asthma, and autoimmune diseases. Here, we review factors controlling mast cell activation, with a focus on receptor signaling and potential therapies for allergic disease. Specifically, we will discuss our work with FcεRI and FγR signaling, IL-4, IL-10, and TGF-β1 treatment, and Stat5. We conclude with potential therapeutics for allergic disease. Much of these efforts have been influenced by the work of Bill Paul. With many mechanistic targets for mast cell activation and different classes of therapeutics being studied, there is reason to be hopeful for continued clinical progress in this area.
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Affiliation(s)
- Heather L Caslin
- Department of Biology, Virginia Commonwealth University, Richmond, VA, United States
| | - Kasalina N Kiwanuka
- Department of Biology, Virginia Commonwealth University, Richmond, VA, United States
| | - Tamara T Haque
- Department of Biology, Virginia Commonwealth University, Richmond, VA, United States
| | - Marcela T Taruselli
- Department of Biology, Virginia Commonwealth University, Richmond, VA, United States
| | - H Patrick MacKnight
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, United States
| | - Anuya Paranjape
- Department of Biology, Virginia Commonwealth University, Richmond, VA, United States
| | - John J Ryan
- Department of Biology, Virginia Commonwealth University, Richmond, VA, United States
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50
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Chiarugi V, Dello Sbarba P, Magnelli L, Chiarugi P, Pacini S, Ruggiero M. Cytokine Receptor Signal Transduction Mechanisms in Immuno-Hematopoietic Cells. TUMORI JOURNAL 2018; 79:92-9. [PMID: 8394037 DOI: 10.1177/030089169307900202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Novel aspects of cytokine receptor signal transduction are discussed and cytokine receptors classified based on ligand-dependent signalling. An introductory section presents an overview of the role of cytokines in hematopoiesis. A brief explanation of basic concepts, such as redundancy, pleiotropy, synergism, etc., important for the understanding of cell response to cytokines, is also included. Three of five classes of receptors show the involvement of tyrosine kinase activity as the key step in signal transduction. The importance of tyrosine phosphorylation in cellular response to cytokines is pointed out.
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Affiliation(s)
- V Chiarugi
- Laboratory of Molecular Biology, University of Florence
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