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.