Interfering with Rap1 function in developing male germ cells leads to reduced fertility owing to a spermiogenetic failure

The small GTPase Rap1 serves as a critical point in signal transduction, somatic cell proliferation and differentiation, and cell cell adhesion through distinct mechanisms. During mouse spermiogenesis, Rap1 is activated and forms a signaling complex with its effector, the serine-threonine kinase B-Raf. To investigate the functional role of Rap1 in male germ cell differentiation, transgenic mice expressing a dominant negative mutant of Rap1 selectively in differentiating spermatids, have been generated. Throughout the phenotypic and biochemical characterization of these mice we found that interfering with Rap1 in haploid male germ cells leads to reduced fertility consistent with an anomalous release of undifferentiating spermatids within the tubule lumen and low sperm counts. These defects correlated with impaired spermatid-Sertoli cell adhesion, also known as apical ectoplasmic specialization (ES). We thus searched, in spermatogenic cells of wild-type and mutant mice, for the presence of adhesion molecules whose function in somatic cells is known to be regulated by Rap1. We found that male germ cells express vascular endothelial cadherin (VE-cadherin) with a timing strictly related to the apical ES formation and function. We, thus, identified VE-cadherin as a molecular component of apical ES. In conclusion, we suggest the possible involvement of cAMP-Epac-Rap1 signaling in the regulation of apical ES dynamics. Our findings may have clinical implications for understanding male infertility in man.