Critical function of RA-GEF-2/Rapgef6, a guanine nucleotide exchange factor for Rap1, in mouse spermatogenesis

•RA-GEF-2 is involved in the regulation of cell adhesion.•RA-GEF-2−/− mice showed marked testicular atrophy and hypospermatogenesis.•RA-GEF-2−/− mice showed significant decrease in sperm concentration and motility.•Severe infertility was observed in RA-GEF-2−/− mice.•RA-GEF-2 may play a crucial role in spermatogenesis via N-cadherin expression. Small GTPase Rap1 has been implicated in the proper differentiation of testicular germ cells. In the present study, we investigated the functional significance of RA-GEF-2/Rapgef6, a guanine nucleotide exchange factor for Rap1, in testicular differentiation using mice lacking RA-GEF-2. RA-GEF-2 was expressed predominantly on the luminal side of the seminiferous tubules in wild-type mice. No significant differences were observed in the body weights or hormonal parameters of RA-GEF-2−/− and wild-type mice. However, the testes of RA-GEF-2−/− male mice were significantly smaller than those of wild-type mice and were markedly atrophied as well as hypospermatogenic. The concentration and motility of epididymal sperm were also markedly reduced and frequently had an abnormal shape. The pregnancy rate and number of fetuses were markedly lower in wild-type females after they mated with RA-GEF-2−/− males than with wild-type males, which demonstrated the male infertility phenotype of RA-GEF-2−/− mice. Furthermore, a significant reduction and alteration were observed in the expression level and cell junctional localization of N-cadherin, respectively, in RA-GEF-2−/− testes, which may, at least in part, account for the defects in testicular differentiation and spermatogenesis in these mice.