Identification of CHD1L as an Important Regulator for Spermatogonial Stem Cell Survival and Self‐Renewal

Abstract

Chromodomain helicase/ATPase DNA binding protein 1-like gene (<i>Chd1l</i>) participates in chromatin-dependent processes, including transcriptional activation and DNA repair. In this study, we have found for the first time that Chd1l is mainly expressed in the testicular tissues of prepubertal and adult mice and colocalized with PLZF, OCT4, and GFR<i>α</i>1 in the neonatal mouse testis and THY1⁺ undifferentiated spermatogonia or spermatogonial stem cells (SSCs). Knockdown of endogenous <i>Chd1l</i> in cultured mouse undifferentiated SSCs inhibited the expression levels of <i>Oct4</i>, <i>Plzf</i>, <i>Gfrα1</i>, and <i>Pcna</i> genes, suppressed SSC colony formation, and reduced BrdU incorporation, while increasing SSC apoptosis. Moreover, the <i>Chd1l</i> gene expression is activated by GDNF in the cultured mouse SSCs, and the GDNF signaling pathway was modulated by endogenous levels of Chd1l; as demonstrated by the gene expression levels of GDNF, inducible transcripts <i>Etv5</i>, <i>Bcl6b</i>, <i>Pou3f</i>, and <i>Lhx1</i>, but not that of GDNF-independent gene, <i>Taf4b</i>, were significantly downregulated by Chd1l knockdown in mouse SSCs. Taken together, this study provides the first evidence to support the notion that <i>Chd1l</i> is an intrinsic and novel regulator for SSC survival and self-renewal, and it exerts such regulation at least partially through a GDNF signaling pathway.