PARENT SESSION

(122) LOSS OF CABLES, A CELL CYCLE-REGULATORY PROTEIN, EXPANDS FOLLICLE NUMBERS IN THE ADULT MOUSE OVARY.

Sakamoto, Hideo^{1, 2}, Luo, Hongwei¹, Kirley, Sandra¹, Lynch, Maureen^{1, 2}, Tilly, Jacqueline^{1, 2}, Zukerberg , Lawrence^{1, 2}, Tilly, Jonathan ^{1, 2}, Rueda, Bo^{1, 2}, ¹ Massachusetts General Hospital, Boston, MA² Harvard Medical School, Boston, MA

ABSTRACT- Cables is a cell cycle inhibitor that also functions as a tumor suppressor in the female reproductive system. Mutant mice lacking Cables develop endometrial hyperplasia at an early age, and endometrial cancer following exposure to chronic estrogen. More recently, we reported that antral follicle recruitment continues in ovaries of Cables deficient mice during pregnancy, resulting in an abnormally high number of antral follicles which is matched by a marked increase in follicular atresia. To further study follicular dynamics in the absence of Cables, we collected ovaries from wild-type (WT) and Cables deficient (knockout, KO) mice during neonatal (day 8) and adult (1.5, 3 and 6 months of age) life. The ovaries were fixed, embedded in paraffin and serially sectioned (8 M). Every fifth section was then assessed for the number of healthy and atretic primordial, primary and small preantral follicles. There was no difference in the number of non-atretic or atretic follicles in WT versus KO mice at day 8. However, by 1.5 months of age there was a significant increase in the number of healthy and atretic preantral follicles in KO ovaries over WT controls. At 3 months of age there were more primordial follicles in KO compared to WT ovaries, but no difference in the number of healthy primary or preantral follicles was observed between the two genotypes. In contrast, there was an increase in the number of atretic preantral follicles in KO mice compared to WT females. By 6 months of age, KO mice possessed significantly more primordial and preantral follicles than WT controls, despite a marked increase in the number of atretic and grossly atretic preantral follicles in the KO females. These findings support recent observations that there occurs a replenishment of the follicle pool in the mammalian ovary, and suggest a prominent role for Cables in modulating cell cycle activity of the stem cell pool responsible for sustaining postnatal oogenesis. This work was supported by RO1-AG024999 (JLT), RO1 CA98333 (BRR) and Vincent Memorial Research Funds (JLT, BRR).

KEY WORDS: OOCYTE, FOLLICLE, CABLES, ATRESIA