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Bax-Dependent Spermatogonia Apoptosis Is Required for Testicular Development and Spermatogenesis¹

^a Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois 62901 ^b Department of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Boston, Massachusetts 02115 ^c Department of Pathology, University of Iowa, Iowa City, Iowa 52241

Bax is a multidomain, proapoptotic member of the Bcl-2 family that is required for normal spermatogenesis in mice. Despite its proapoptotic function, previous results found that Bax-deficient mature male mice demonstrate increased cell death and dramatic testicular atrophy. The present study examined the role of Bax during the normal development of the testis to determine whether the increased cell death in mature mice could be explained by decreased apoptosis earlier in development. Consistent with this hypothesis, testicular atrophy is preceded by increased testicular weight and hypercellular tubules in immature Bax-deficient mice. TUNEL staining at Postnatal Day (P) 7 and morphological quantitation between P5 and P15 demonstrates decreased germ cell apoptosis in Bax-deficient mice. By P15, increased numbers of type A spermatogonia, and at P12 and P15, an increase in intermediate type spermatogonia were noted in Bax-deficient animals. By P25, the number of basal compartment cells was greatly increased in Bax-deficient animals compared with controls such that four or five layers of preleptotene spermatocytes were routinely present within the basal compartment of the testis. Although the Sertoli cell barrier was significantly removed from the basement membrane, it appeared intact as judged by the hypertonic fixation test. During late pubertal development, massive degeneration of germ cells took place, including many of those cell types that previously survived in the first wave of spermatogenesis. The data indicate that Bax is required for normal developmental germ cell death in the type A spermatogonia, specifically dividing (A₂, A₃, and A₄) spermatogonia, at a time at which the number of spermatogonia is regulated in a density-dependent manner. The massive hyperplasia that occurs in Bax-deficient mice subsequently results in Bax independent cell death that may be triggered by overcrowding of the seminiferous epithelium.

First decision: 31 July 2001.

¹ We acknowledge National Institutes of Health grants HD 35494 to L.D.R. and R01 CA50293 to S.J.K., a Latin American Fellowship to H.C.-G., and the Howard Hughes Medical Institute grant RRP 76292-550301 to C.M.K. C.M.K. is a Charles E. Culpeper Medical Scholar and the work was supported by the Rockefeller Brothers Fund.

² Correspondence. FAX: 319 335 6555; c-knudson{at}uiowa.edu

³ Current address: Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Brazil 31270-901

⁴ Deceased.

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