ARID4B is an essential coordinator of spermatogonial stem cell function and spermatogenesis Open Access
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Spermatogonial stem cells (SSCs) have the ability to undergo self-renewal or spermatogenic differentiation to generate spermatozoa. The SSC capability and spermatogenic progression are dependent on optimal microenvironment. Although it has been reported that Sertoli cells responsible for a SSC niche establishment and support of spermatogenesis, the factors and mechanisms that regulate such activities of Sertoli cells are still unclear. Here, we discovered an important role of AT-rich interactive domain 4B (ARID4B) in Sertoli cell function to regulate spermatogenic cell fate, using the Sertoli cell-specific Arid4b knockout (Arid4bSCKO) mice. During neonatal and peripubertal periods, Sertoli cells in the Arid4bSCKO testes underwent extensive apoptosis and failed to establish the SSC niche, which affected SSC survival, self-renewal, and differentiation, resulting to deletion of germ cells. We found that ARID4B is a survival factor in Sertoli cells, at least partly, by suppressing the p53 apoptosis pathway. Moreover, ARID4B is required for Sertoli cells to support the progression of spermatogenesis. During puberty and postpubertal periods, the Arid4bSCKO testes exhibited prolonged Sertoli cell maturation along with delayed onset of spermatogenesis and a block in spermatid elongation. Importantly, we found that ARID4B is involved in activation of the androgen receptor (AR) signal pathway, as deletion of ARID4B down-regulated Rhox5, an AR target gene critical for spermatogenesis. Our study defined a dual role of ARID4B, as a `corepressor' of p53 to protect Sertoli cell survival for preserving the SSC ability, and as a `coactivator' of AR to ensure Sertoli cell function for supporting spermatogenic differentiation.