Abstract
Chromodomain helicase/ATPase DNA binding protein 1-like gene (Chd1l) 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 GFRα1 in the neonatal mouse testis and THY1+ undifferentiated spermatogonia or spermatogonial stem cells (SSCs). Knockdown of endogenous Chd1l in cultured mouse undifferentiated SSCs inhibited the expression levels of Oct4, Plzf, Gfrα1, and Pcna genes, suppressed SSC colony formation, and reduced BrdU incorporation, while increasing SSC apoptosis. Moreover, the Chd1l 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 Etv5, Bcl6b, Pou3f, and Lhx1, but not that of GDNF-independent gene, Taf4b, were significantly downregulated by Chd1l knockdown in mouse SSCs. Taken together, this study provides the first evidence to support the notion that Chd1l 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.
Highlights
Chromodomain helicase/ATPase DNA binding protein 1like gene (Chd1l), which encodes an unexplored chromatin remodeling factor with a similar domain to that of SNF2 gene family, is originally reported in liver cancer and functions as an oncogene [1]
Data from Quantitative real-time reverse transcription PCR (qRT-PCR) analyses showed that the expression levels of Chd1l transcript in postnatal mice testis were gradually increased from 5 dpp to adulthood (56 dpp)
CHD1L protein expression displayed a similar trend to its mRNA transcript before puberty as demonstrated in Western Blotting analyses, a much lower level was observed at the adult stage (Figure 1(c))
Summary
Chromodomain helicase/ATPase DNA binding protein 1like gene (Chd1l), which encodes an unexplored chromatin remodeling factor with a similar domain to that of SNF2 gene family, is originally reported in liver cancer and functions as an oncogene [1]. The continual process of spermatogenesis depends on the self-renewal and differentiation potency of spermatogonial stem cells (SSCs) throughout the mammalian whole life. Several other transcription factors (e.g., Nanog, Plzf, Bcl6b, Pou3f, and Etv5) have been reported to regulate SSC self-renewal [14,15,16,17]. Some GDNF-independent factors (e.g., Plzf, Taf4b, Foxo, Stem Cells International and Pou5f1) [18, 19] and the autocrine Hedgehog (Hh) signaling loop [20] have been recently suggested to sustain undifferentiated spermatogonia cells, suggesting that spermatogenesis is closely regulated by a fine and complicated regulatory network. To gain some insights into the functions of CHD1L in spermatogenesis, in this study, we have observed that CHD1L is coexpressed with the established markers of undifferentiated spermatogonia (GFRα1, PLZF) and the pluripotency factor OCT4 in newborn and adult testes of mice. Using a Chd1l-short hairpin RNA (shRNA) approach, we have further unraveled a novel functional role of Chd1l in SSC self-renewal and survival
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