Regulation of Cell Fate Decision of Undifferentiated Spermatogonia by GDNF

TLDR

The molecular mechanisms governing stem cell self‑renewal and differentiation remain poorly understood. Transgenic loss‑of‑function and overexpression studies demonstrate that Sertoli‑cell–derived GDNF dosage controls the fate of undifferentiated spermatogonia, including spermatogonial stem cells. Mice with a single GDNF‑null allele exhibit depleted spermatogonial stem cell reserves, whereas GDNF overexpression causes accumulation of undifferentiated spermatogonia that fail to differentiate, undergo retinoic‑acid‑induced apoptosis, and predispose older mice to nonmetastatic testicular tumors, underscoring GDNF’s role in paracrine regulation of spermatogonial self‑renewal and differentiation.

Abstract

The molecular control of self-renewal and differentiation of stem cells has remained enigmatic. Transgenic loss-of-function and overexpression models now show that the dosage of glial cell line–derived neurotrophic factor (GDNF), produced by Sertoli cells, regulates cell fate decisions of undifferentiated spermatogonial cells that include the stem cells for spermatogenesis. Gene-targeted mice with one GDNF -null allele show depletion of stem cell reserves, whereas mice overexpressing GDNF show accumulation of undifferentiated spermatogonia. They are unable to respond properly to differentiation signals and undergo apoptosis upon retinoic acid treatment. Nonmetastatic testicular tumors are regularly formed in older GDNF-overexpressing mice. Thus, GDNF contributes to paracrine regulation of spermatogonial self-renewal and differentiation.