Mouse CHD4-NURD is required for spermatogonia survival and normal meiotic progression

Testis development and sustained germ cell production in adults rely on the establishment and maintenance of spermatogonia stem cells and their proper differentiation into spermatocytes, which through two consecutive cell divisions produce mature gametes. The chromatin remodeling complexes regulate critical processes in both premeiotic and meiotic stages of gamete development by restricting or promoting accessibility of DNA repair and gene expression machineries to the chromatin. Here, we investigated the role of the NUcleosome Remodeling and Deacetylase (NURD) complex during spermatogenesis. Our cellular and biochemical analyses revealed differential expression and composition of NURD subunits in germ cells at different stages of testis development. Germ cell-specific deletion early in gametogenesis of the NURD catalytic component Chd4, but not Chd3, resulted in arrested early gamete development due to failed cell survival of neonate undifferentiated spermatogonia stem cell population. Candidate assessment revealed that CHD4 controls Dmrt1 and its downstream target Plzf, both described as prominent regulators of spermatogonia stem cell maintenance. Further, deletion of Chd4 at meiotic relevant stages of gamete development resulted in spermatocyte arrest at a zygotene-like stage, with apparent deficient double-strand break repair and abnormal homologous chromosome synapsis. Together, our results uncover a dual requirement of CHD4 in mammalian gametogenesis and point to unique functions for the NURD complex with respect to other chromatin remodelers during gamete development.