BCLW mediates survival of postmitotic Sertoli cells by regulating BAX activity

Male mice deficient in BCLW, a death-protecting member of the BCL2 family, are sterile due to an arrest in spermatogenesis that is associated with a g radual loss of germ cells and Sertoli cells from the testis. As Bclw is exp ressed in both Sertoli cells and diploid male germ cells, it has been uncle ar which of these cell types requires BCLW in a cell-autonomous manner for survival. To determine whether death of Sertoli cells in Bclw mutants is in fluenced by the protracted loss of germ cells, we examined testes from Bclw /c-kit double mutant mice, which lack germ cells from birth. Loss of BCLW-d eficient Sertoli cells occurs in the absence of germ cells, indicating that germ cell death is not required to mediate loss of Sertoli cells in BCLW-d eficient mice. This suggests that Sertoli cells require BCLW in a cell-intr insic manner for long-term survival. The loss of Sertoli cells in Bclw muta nts commences shortly after Sertoli cells have become postmitotic. In situ hybridization analysis indicates that Bclw is expressed in Sertoli cells bo th before and after exit from mitosis. Therefore, Bclw-independent pathways promote the survival of undifferentiated, mitotic Sertoli cells. We show t hat BAX and BAK, two closely related death-promoting members of the BCL2 fa mily, are expressed in Sertoli cells. To determine whether either BAX or BA K activity is required for Sertoli cell death in Bclw mutant animals, we an alyzed survival of Sertoli cells in Bclw/Bax and Bclw/Bak double homozygous mutant mice. While mutation of Bak had no effect, ablation of Bax suppress ed the loss of Sertoli cells in Bclw mutants. Thus, BCLW mediates survival of postmitotic Sertoli cells in the mouse by suppressing death-promoting ac tivity of BAX. (C) 2001 Academic Press.