Hyal‐1 but not hyal‐3 deficiency has an impact on ovarian folliculogenesis and female fertility by altering the follistatin/activin/Smad3 pathway and the apoptotic process

Ovarian follicle development is a process regulated by various endocrine, paracrine and autocrine factors that act coordinately to promote follicle growth. However, the vast majority of follicles does not reach the pre‐ovulatory stage but instead, undergo atresia by apoptosis. We have recently described a role for the somatic hyaluronidases (Hyal‐1, Hyal‐2, and Hyal‐3) in ovarian follicular atresia and induction of granulosa cell apoptosis. Herein, we show that Hyal‐1 but not Hyal‐3 null mice have decreased apoptotic granulosa cells after the induction of atresia and an increased number of retrieved oocytes after stimulation of ovulation. Furthermore, young Hyal‐1 null mice had a significantly higher number of primordial follicles than age matched wild‐type animals. Recruitment of these follicles at puberty resulted in an increased number of primary and healthy preantral follicles in Hyal‐1 null mice. Consequently, older Hyal‐1 deficient female mice have prolonged fertility. At the molecular level, immature Hyal‐1 null mice have decreased mRNA expression of follistatin and higher levels of phospho‐Smad3 protein, resulting in increased levels of phospho‐Akt in pubertal mice. Hyal‐1 null ovarian follicles did not exhibit hyaluronan accumulation. For Hyal‐3 null mice, compensation by Hyal‐1 or Hyal‐2 might be related to the lack of an ovarian phenotype. In conclusion, our results demonstrate that Hyal‐1 plays a key role in the early phases of folliculogenesis by negatively regulating ovarian follicle growth and survival. Our findings add Hyal‐1 as an ovarian regulator factor for follicle development, showing for the first time an interrelationship between this enzyme and the follistatin/activin/Smad3 pathway. J. Cell. Physiol. 227: 1911–1922, 2012. © 2011 Wiley Periodicals, Inc.