title: Deletion of MgcRacGAP in the male germ cells impairs spermatogenesis and causes male sterility in the mouse.
abstract: MgcRacGAP (RACGAP1) is a GTPase Activating Protein (GAP), highly produced in the mouse embryonic brain and in the human and mouse post-natal testis. MgcRacGAP negatively controls the activity of Rac and Cdc42, which are key molecular switches acting on the microtubule and actin cytoskeleton and controlling various cell processes such as proliferation, adhesion and motility. Previous studies demonstrated that MgcRacGAP plays a critical role in the cytokinesis of somatic cells; hence homozygous inactivation of the gene in the mouse and mutation in Caenorhabditis elegans led to embryonic lethality due to the inability of MgcRacGAP-null embryos to assemble the central spindle and to complete cytokinesis. In the testis, the germ cells do not complete cytokinesis and remain connected as a syncytium throughout the entire process of spermatogenesis. Interestingly, MgcRacGAP was shown to locate to the intercellular bridges, connecting these germ cells. In order to determine the function(s) of MgcRacGAP in the male germline, we generated a conditional knock-out mouse using Stra8 promoter driven Cre recombinase to induce the specific deletion of MgcRacGAP in the pre-meiotic germ cells. We found that the absence of MgcRacGAP induced a germline depletion and male sterility. Consistent with the role of MgcRacGAP in the establishment of the cytoplasm constriction during cytokinesis of the somatic cells, we observed that MgcRacGAP deletion in the germ cells prevented the formation of the intercellular bridges and induced a proliferation arrest. While we assume that inherited homozygous loss of function mutations in MgcRacGAP would be lethal in human, de novo mutations in the testis might account for some cases of non-obstructive oligo- and/or azoo-spermia syndromes, whose genetic causes are altogether still poorly defined.
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75014 Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lorès
authors.affiliation: Department of functional genomics and cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch Cedex, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Vernet
authors.affiliation: Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Japan; Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.affiliation: Laboratory of Molecular Biology (Celgen), Department Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Van de Putte
authors.affiliation: Laboratory of Molecular Biology (Celgen), Department Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Danny
authors.initials: D
authors.lastname: Huylebroeck
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, AK Project, 606-8501 Kyoto, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Hikida
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75014 Paris, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Gacon
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75014 Paris, France. Electronic address: aminata.toure@inserm.fr.
authors.forename: Aminata
authors.initials: A
authors.lastname: Touré
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020690:GTPase-Activating Proteins / Q000172:deficiency*; D005854:Germ Cells / Q000737:chemistry*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology*; D013737:Testis / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D020690:GTPase-Activating Proteins; C115995:mgcRacGAP
keywords: Knock out mouse model; Male infertility; MgcRacGAP; Spermatogenesis; Testis