The Influence Of Sertoli Cell Dependant Structure And Function On Germ Cell Development

Spermatogenesis is a complex developmental process that ultimately generates mature spermatozoa, which includes spermatogonial stem cell self-renewal and differentiation, spermatocyte meiosis and spermiogenesis. Any abnormalility in this process will lead to sperm formation reduction (such as oligospermia) or even unable to form (sucha as azoospermia), which ultimately lead to infertility. In spermatogenesis, germ cells at every stage should be keeping direct contact with the Sertoli cells and depend on the structure support, signal and microenvironment that provided by Sertoli cells. However, the mechanisms that Sertoli cells regulate different stage germ cell development is still unclear during spermatogenesis.In this research, Sertoli cell specific gene (Cdh2, Cx43, Racl and Npat) knockout mice were used to study the effect and mechanism of cell junction, communication and microenvironment on the development of germ cells.We found that during mouse testis development, the blood testis barrier adhesion gene Cdh2deficiency in germ cells do not affect spermatogenesis, but its specific knockout in Sertoli cells cause the blood testis barrier dysfunction, meiotic delay, apoptosis increasing and spermatocyte slough, eventually led to sperm reduction and subfertility.When Cdh2and gap junction gene Cx43double knockout in Sertoli cells, the resulted phenotye in spermatogenesis which is not entirely consistent with the knockout of Cdh2or Cx43alone in Sertoli cells, indicating that the blood testis barrier components (such as gap junction and adhesion junction) employ different pathway to regulate spermatogenesis, and this regulation may be associated with β-catenin expression in Sertoli cells.In addition, Racl in germ cells that have not pass through the blood testis barrier, such as spermatogonial stem cells or spermatogonia is dispensible for spermatogenesis, but deletion of Racl in Sertoli cells leads to Sertoli cell number reduction, cytoskeleton disorganization, leptotene spermatocyte apoptosis, meiosis hindered, and resulted in meiotic prophase spermatocyte decreasing and eventually spermatogenic abnormality. Finally, deletion of Npat in the embryonic Sertoli cells leads to seminiferou tubule number reduce and testicular degeneration.These results proved that Sertoli cells affect germ cell development at various stages. For example, Npat deletion in Sertoli cells cannot maintain the gonocyte survival; Cdh2and Cx43double knockout in Sertoli cells leads to abnormal differentiation of spermatogonial stem cells and slough of spermatocytes; Sertoli cell specific deletion of Racl leads to apoptosis of prepubtal spermatocyte; Cdh2knockout in Sertoli cells will cause early spermatocyte disengagement. Consequently, germ cell development abnormaliyt at any stage will cause spermatogenetic disorder and eventually lead to subfertility or sterility in mice.In summary, we found that Sertoli cells play an important role during spermatogenesis through different Sertoli cell specific gene knockout mice. The Sertoli cell dependent cell junctions, cell communications and microenvironment change may lead to germ cell development abnormality and eventually reproductive disorders. So these findings provide a new theoretical basis for revealing the pathogenesis of human spermatogenesis such as oligozoospermia and azoospermia and point out a new direction for future diagnosis and treatment of human infertility.