Regulation of spermatogonial stem cell self-renewal and proliferation in mammals.

The generation of functional sperm relies on spermatogonial stem cells (SSCs) as they can maintain a stem cell pool for continuous generation of functional spermatozoa. The maintenance of SSCs is regulated by several factors. In this paper, we summarize the niche and intrinsic factors in regulating SSC self-renewal and proliferation. GDNF regulates SSC self-renewal through Ras-ERK1/2, SFC, PI3K/Akt and MEK/ERK-mTOR signaling pathways. FGF activates MAPK2K1, ERK and Akt pathways and EGF activates ERK and Akt pathways to induce SSC proliferation. Wnt ligands regulate SSC self-renewal and proliferation through both β-catenin dependent and independent pathways. SCF1 and CXCL12 are also found to have roles in SSC maintenance. As for intrinsic factors in SSCs, ETV5, Bcl6b, Lhx1, ID4 and Nanos2 are regulated by niche factors. They act as the downstream factors of niche factors in regulating SSC self-renewal and proliferation. Transcriptional factors OCT4 and PLZF, as well as FOXO1 in SSCs can directly regulate SSC self-renewal and proliferation. Although we have identified the factors, the detailed mechanism of these factors in regulating SSC fate determination is largely unknown. Here, we summarize factors which have roles in SSC fate determination and hope it will be beneficial for further study and treatment of male infertility.