Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice
| Autor: | Taiping Chen, John H. Richburg, Sharon Y.R. Dent, Raif S. Geha, Jean Louis Guénet, Caitlin J. Murphy, Carlos J. Perez, Janet Chou, Jean Jaubert, Tewfik Hamidi, Meichun Deng, Craig D. Platt, Qinghua Shi, Yue Lu, Héctor Gaitán-Peñas, Fernando Benavides, Kevin Lin, Jeesun Kim, Hui Lin Pan, Mark T. Bedford, Jianqiang Bao, Meng Hua Zhou, Huan Zhang, Yuying Huang, Raúl Estévez |
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| Přispěvatelé: | The University of Texas M.D. Anderson Cancer Center [Houston], School of Life Science [Heifei], University of Science and Technology of China [Hefei] (USTC), University of Texas at Austin [Austin], Génétique de la souris - Mouse Genetics, Institut Pasteur [Paris], Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Center for Neuroscience & Pain Research [Houston], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Enfermedades Raras (CIBERER), Graduate School of Biomedical Sciences [Houston], The University of Texas Health Science Center at Houston (UTHealth)-The University of Texas M.D. Anderson Cancer Center [Houston], This study made use of the Research Animal Support Facility-Smithville (including Laboratory Animal Genetic Services and Research Histology Pathology and Imaging Core), the Sequencing and Microarray Facility, and the HREMF, all of which are supported by P30 CA016672 DHHS/NCI Cancer Center Support Grant to MD Anderson Cancer Center. This work was supported in part by Departmental Funds and Molecular Biology Facility Core supported by CPRIT grant RP170002 to Dr. Jianjun Shen, National Basic Research Program of China (2014CB943101) and the National Natural Science Foundation of China (31371519 and 313111245) to QS, and R01 ES016591 to JHR., We thank the Research Animal Support Facility-Smithville for their assistance with the maintenance of the mouse strains, the Histology Core for processing the samples, the Molecular Biology Facility Core for RNA sequencing, the Bioinformatics and Biostatistics Services for data analysis, and Briana Dennehey for editing the manuscript., Institut Pasteur [Paris] (IP) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine MESH: Membrane Proteins / genetics medicine.disease_cause MESH: Mice Knockout Male infertility Mice MESH: Testis / pathology Testis MESH: Animals MESH: Membrane Proteins / metabolism MESH: Healthy Volunteers MESH: Infertility Male / diagnosis Mice Knockout Reproductive Biology Mutation biology Esterilitat en els animals General Medicine Anion channel activity MESH: Biological Transport Active / genetics Spermatozoa MESH: Case-Control Studies Healthy Volunteers MESH: China MESH: Spermatozoa / cytology MESH: Biomarkers / analysis Cell biology medicine.anatomical_structure Flagella MESH: Cell Survival / genetics Ion channels Sperm Motility Female Germ cell Research Article Adult Anions China endocrine system MESH: Mutation Cell Survival Sterility Biological Transport Active MESH: Spermatozoa / pathology 03 medical and health sciences Infertility in animals Genetics medicine Animals Humans MESH: Mice Infertility Male MESH: Ion Transport / genetics MESH: Infertility Male / pathology Ion Transport MESH: Humans MESH: Sperm Motility / genetics Membrane Proteins MESH: Adult medicine.disease Sperm MESH: Male MESH: Anions / metabolism Disease Models Animal [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics Insulin receptor Fertility MESH: Flagella / pathology 030104 developmental biology Apoptosis Case-Control Studies biology.protein MESH: Disease Models Animal MESH: Infertility Male / genetics MESH: Female Biomarkers |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona JCI Insight JCI Insight, American Society for Clinical Investigation, 2018, 3 (16), pp.e99767. ⟨10.1172/jci.insight.99767⟩ JCI Insight, 2018, 3 (16), pp.e99767. ⟨10.1172/jci.insight.99767⟩ |
| ISSN: | 2379-3708 |
| Popis: | International audience; Ion channel-controlled cell volume regulation is of fundamental significance to the physiological function of sperm. In addition to volume regulation, LRRC8A-dependent volume-regulated anion channel (VRAC) activity is involved in cell cycle progression, insulin signaling, and cisplatin resistance. Nevertheless, the contribution of LRRC8A and its dependent VRAC activity in the germ cell lineage remain unknown. By utilizing a spontaneous Lrrc8a mouse mutation (c.1325delTG, p.F443*) and genetically engineered mouse models, we demonstrate that LRRC8A-dependent VRAC activity is essential for male germ cell development and fertility. Lrrc8a-null male germ cells undergo progressive degeneration independent of the apoptotic pathway during postnatal testicular development. Lrrc8a-deficient mouse sperm exhibit multiple morphological abnormalities of the flagella (MMAF), a feature commonly observed in the sperm of infertile human patients. Importantly, we identified a human patient with a rare LRRC8A hypomorphic mutation (c.1634G>A, p.Arg545His) possibly linked to Sertoli cell-only syndrome (SCOS), a male sterility disorder characterized by the loss of germ cells. Thus, LRRC8A is a critical factor required for germ cell development and volume regulation in the mouse, and it might serve as a novel diagnostic and therapeutic target for SCOS patients. |
| Databáze: | OpenAIRE |
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