Effects of a Sertoli cell specific knockout of the connexin43-gene on the regulation of spermatogenesis in transgenis mice using the Cre/IoxP-recombination system
Final Report Abstract
A significant decline in human male reproductive function has been reported for the past 20 years but the molecular mechanisms remain poorly understood. However, recent studies showed that the gap junction protein Connexin43 (Cx43) might be involved as Cx43 is the predominant testicular Cx in most species including men. Alterations of its expression are associated with different forms of spermatogenic disorders and infertility and many human patients with impaired spermatogenesis exhibit a reduction or loss of Cx43 expression in GC and SC. Adult male transgenic mice with a conditional KO of the Gja1 gene in SC (SCCx43KO) show a comparable testicular phenotype and are infertile. To detect possible signalling pathways and molecular mechanisms leading to the testicular phenotype in adult SCCx43KO mice and to their failure to initiate spermatogenesis, the testicular gene expression of eight day old SCCx43KO and wild-type (WT) mice was compared. Microarray analysis revealed that 658 genes were significantly regulated in testes of SCCx43KO mice. Of these genes, 135 were up-regulated while 523 genes were down-regulated. The majority of the down-regulated genes are GC specific and essential for mitotic and meiotic progression of spermatogenesis including Stra8, Dazl and members of the DM (DM=dsx and map-3) gene family. Other altered genes can be associated with transcription, metabolism, cell migration and cytoskeleton organization. Our data show that deletion of Cx43 in SC leads to multiple alterations of gene expression in pre-pubertal mice and affects primarily the GC. The candidate genes may represent helpful markers for investigators exploring human testicular biopsies from patients showing corresponding spermatogenic deficiencies and studying the molecular mechanisms of human male sterility. Among different transgenic mouse models that are used to elucidate the versatile reasons for human male infertility, the SCCx43KO mice do provide a unique model for the identification of candidate genes in GC that can be associated with human male factor infertility and impaired spermatogenesis.
