HDAC3 promotes Sertoli cell maturation and maintains the blood-testis barrier dynamics

Germ cell development depends on the capacity of somatic Sertoli cells to undergo differentiation into a mature state and establish a germ cell-specific blood-testis barrier (BTB). The BTB structure confers an immunological barrier for meiotic and postmeiotic germ cells, and its dynamic permeability facilitates a transient movement of preleptotene spermatocytes through BTB to enter meiosis. However, the regulatory factors involved in Sertoli cell maturation and how BTB dynamics coordinate germ cell development remain unclear. Here, we found a histone deacetylase HDAC3 abundantly expresses in Sertoli cells and localizes in both cytoplasm and nucleus. Sertoli cell-specific Hdac3 knockout in mice causes infertility with compromised integrity of blood-testis barrier, leading to germ cells unable to traverse through BTB and an accumulation of preleptotene spermatocytes in juvenile testis. Mechanistically, nuclear HDAC3 regulates the expression program of Sertoli cell maturation genes, and cytoplasmic HDAC3 forms a complex with the gap junction protein Connexin 43 to modulate the BTB integrity and dynamics through regulating the distribution of tight junction proteins. Our findings identify HDAC3 as a critical regulator in promoting Sertoli cell maturation and maintaining the homeostasis of the blood-testis barrier. Sertoli cells establish a germ cell-specific blood-testis barrier (BTB) that ensures an immunological barrier and transiently facilitates the movement of preleptotene spermatocytes through the BTB. The histone deacetylase HDAC3 is present both in the nucleus and cytoplasm of Sertoli cells, and forms a protein complex with the gap junction protein Cx43 to modulate the BTB dynamics through regulating the distribution of tight junction proteins. The depletion of Sertoli HDAC3 impairs the BTB homeostasis that eventually results in defects in spermatogenesis.image