Nature Genetics
21, 200 - 203 (1999)
doi:10.1038/5985
Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiencyGloria I. Perez1, 4, Rodolfo Robles1, 4, C. Michael Knudson2, Jodi A. Flaws1, 3, Stanley J. Korsmeyer2
& Jonathan L. Tilly11
Vincent Center for Reproductive Biology, Massachusetts General Hospital and Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts 02114, USA. 2
Howard Hughes Medical Institute and Division of Molecular Oncology, Departments of Medicine and Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. 3
Department of Epidemiology and Preventative Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Jonathan L. Tilly tilly.jonathan@mgh.harvard.eduFemale mammals are endowed with a finite number of oocytes at birth, each enclosed by a single layer of somatic (granulosa) cells in a primordial follicle1,
2. The fate of most follicles is atretic degeneration1,
3, a process that culminates in near exhaustion of the oocyte reserve at approximately the fifth decade of life in women, leading to menopause4,
5. Apoptosis has a fundamental role in follicular atresia6,
7, and recent studies have shown that Bax, which is expressed in both granulosa cells8,
9 and oocytes10, may be central to ovarian cell death6,
7,
8,
9,
10,
11,
12. Here we show that young adult female Bax−/− mice possess threefold more primordial follicles in their ovarian reserve than their wild−type sisters, and this surfeit of follicles is maintained in advanced chronological age, such that 20−22−month−old female Bax−/− mice possess hundreds of follicles at all developmental stages and exhibit ovarian steroid−driven uterine hypertrophy. These observations contrast with the ovarian and uterine atrophy seen in aged wild−type female mice. Aged female Bax−/− mice fail to become pregnant when housed with young adult males; however, metaphase II oocytes can be retrieved from, and corpora lutea form in, ovaries of aged Bax−/− females following superovulation with exogenous gonadotropins, and some oocytes are competent for in vitro fertilization and early embryogenesis. Therefore, ovarian lifespan can be extended by selectively disrupting Bax function, but other aspects of normal reproductive performance remain defective in aged Bax−/− female mice.
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