title: 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.
abstract: 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.
authors: Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada.
authors: Karine
authors: K
authors: Dumaresq-Doiron
authors: Lydia
authors: L
authors: Edjekouane
authors: Adriana Mari
authors: AM
authors: Orimoto
authors: Paule Héléna
authors: PH
authors: Yoffou
authors: Lara
authors: L
authors: Gushulak
authors: Barbara
authors: B
authors: Triggs-Raine
authors: Euridice
authors: E
authors: Carmona
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D005260:Female; D005298:Fertility / Q000502:physiology*; D005496:Follicular Atresia / Q000378:metabolism; D038681:Follistatin / Q000378:metabolism*; D006107:Granulosa Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000172:deficiency* / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009865:Oocytes / Q000166:cytology; D006080:Ovarian Follicle / Q000166:cytology / Q000254:growth & development* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D038681:Follistatin; D007527:Isoenzymes; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D028341:Activins; C469220:Hyal1 protein, mouse; D006821:Hyaluronoglucosaminidase