Regulation of spermatogonial stem cell behavior in vivo and in vitro1

Spermatogonial stem cells (SSCs) are one of the best studied types of stem cells with respect to cellular aspects and new data on the molecular pathways regulating their behavior now become available frequently. In non-primate mammals, SSCs have been identified as single spermatogonia that either selfrenew, by dividing into two new single spermatogonia, or differentiate by giving rise to a pair of spermatogonia connected by an intercellular bridge. After cell loss, selfrenewing divisions of SSCs are strongly preferred implicating the existence of regulatory mechanisms that govern the ratio of selfrenewal and differentiation. Glial cell line derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2), both secreted by Sertoli cells, have been found to enhance SSC selfrenewal. The secretion of GDNF is controlled by FSH. The action of GDNF on SSCs is mediated by its receptors c-Ret and GFRalpha1 and involves the transcriptional repressor Bcl6b. Furthermore, Plzf, like Bcl6b a member of the POZ domain containing proteins, is also involved in enhancing SSC self-renewal but along another as yet unknown pathway. Finally, in vitro studies revealed that the Sertoli cell proteins activin A and BMP4 likely stimulate SSC differentiation. Hence, Sertoli cells produce both factors that promote selfrenewal and factors that promote differentiation. The mechanisms that regulate the proper balance in the secretion of these factors with opposing actions by Sertoli cells, are at present unknown