Spermatogenesis in Bclw-deficient mice

Bclw is a death-protecting member of the Bcl2 family of apoptosis-regulatin g proteins. Mice that are mutant for Bclw display progressive and nearly co mplete testicular degeneration. We performed a morphometric evaluation of t esticular histopathology in Bclw-deficient male mice between 9 days postnat al (p9) through 1 yr of age. Germ cell loss began by p22, with only few ger m cells remaining beyond 7 mo of age. A complete block to elongated spermat id development at step 13 occurred during the first wave of spermatogenesis , whereas other types of germ cells were lost sporadically. Depletion of Se rtoli cells commenced between p20 and p23 and continued until 1 yr of age, when few, if any, Sertoli cells remained. Mitochondria appeared to be swoll en and the cytoplasm dense by electron microscopy, but degenerating Bclw-de ficient Sertoli cells failed to display classical features of apoptosis, su ch as chromatin condensation and nuclear fragmentation. Macrophages entered seminiferous tubules and formed foreign-body giant cells that engulfed and phagocytosed the degenerated Sertoli cells. Leydig cell hyperplasia was ev ident between 3 and 5 mo of age. However, beginning at 7 mo of-age, Leydig cells underwent apoptosis, with dead cells being phagocytosed by macrophage s. The aforementioned cell losses culminated in a testis-containing vascula ture, intertubular phagocytic cells, and peritubular cell "ghosts." An RNA in situ hybridization study indicates that Bclw is expressed in Sertoli cel ls in the adult mouse testis. Consequently, the diploid germ cell death may be an indirect effect of defective Sertoli cell function. Western analysis was used to confirm that BclW is not expressed in spermatids; thus, loss o f this cell type most likely results from defective Sertoli cell function. Because BclW does not appear to be expressed in Leydig cells, loss of Leydi g cells in Bclw-deficient mice:may result from depletion of Sertoli cells. Bclw-deficient mice serve as a unique model to study homeostasis of cell po pulations in the testis.