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Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency

Nature Genetics volume 21, pages 200–203 (1999)Cite this article

Abstract

Female 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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Figure 1: Uterine histology in aged female wild–type and Bax–/– mice.
Figure 2: Ovarian histology in aged female wild–type and Bax–/– mice.
Figure 3: Ovarian histology of aged Bax–/– female mice following superovulation.
Figure 4: Non–atretic follicle numbers in wild–type and Bax–/– female mice throughout life.
Figure 5: Histomorphometric analysis of atretic follicles in wild–type and Bax–/– female mice.

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Acknowledgements

We thank I. Schiff for critical reading of the manuscript before its submission. C.M.K. was supported as a Pfizer Postdoctoral Fellow and G.I.P. was supported in part by the Massachusetts General Hospital Fund for Medical Discovery and the Harvard Medical School Janet M. McArthur Fellowship. This study was supported by research grants from the National Institutes of Health to J.L.T. (R01–AG12279, R01–HD34226) and S.J.K. (R01–CA49712), and by Vincent Memorial Research Funds.

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  1. Gloria I. Perez and Rodolfo Robles: These authors contributed equally to this work.

Authors and Affiliations

  1. Massachusetts General Hospital and Department of Obstetrics, Vincent Center for Reproductive Biology, Gynecology and Reproductive Biology, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Gloria I. Perez, Rodolfo Robles, Jodi A. Flaws & Jonathan L. Tilly

  2. Howard Hughes Medical Institute and Division of Molecular Oncology, Departments of Medicine and Pathology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    C. Michael Knudson & Stanley J. Korsmeyer

  3. Department of Epidemiology and Preventative Medicine, University of Maryland School of Medicine, Baltimore, 21201, Maryland, USA

    Jodi A. Flaws

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  1. Gloria I. Perez
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Correspondence to Jonathan L. Tilly.

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Perez, G., Robles, R., Knudson, C. et al. Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nat Genet 21, 200–203 (1999). https://doi.org/10.1038/5985

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