Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency.
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 follicle. The fate of most follicles is atretic degeneration, a process that culminates in near exhaustion of the oocyte reserve at approximately the fifth decade of life in women, leading to menopause. Apoptosis has a fundamental role in follicular atresia, and recent studies have shown that Bax, which is expressed in both granulosa cells and oocytes, may be central to ovarian cell death. 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.
Perez
G I
GI
Vincent Center for Reproductive Biology, Massachusetts General Hospital and Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston 02114, USA.
Robles
R
R
Knudson
C M
CM
Flaws
J A
JA
Korsmeyer
S J
SJ
Tilly
J L
JL
D000375:Aging / Q000502:physiology*; D000818:Animals; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D005260:Female; D005854:Germ Cells / Q000502:physiology; D006984:Hypertrophy; D051379:Mice; D018345:Mice, Knockout; D006080:Ovarian Follicle / Q000502:physiology; D010053:Ovary / Q000166:cytology / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D013480:Superovulation / Q000235:genetics / Q000502:physiology; D014599:Uterus / Q000473:pathology; D051028:bcl-2-Associated X Protein