Early oocyte loss following genome integrity disruption leads to ovarian remodeling associated with maintained estrogen production, sexual receptivity and patterns of estrus cyclicity

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 515-547-Female Reproductive Endocrinology
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-515
Joelle Cohen-Tannoudji*1, Sandrine Vandormael-Pournin2, Céline Julie Guigon1, Muhammad Ishaq1, Noelline Coudouel1, Michel Huerre3, Patrick Avé3, Solange Magre1 and Michel Cohen-Tannoudji2
1University Paris 7, France, 2Unité de Génétique Fonctionnelle de la Souris, Institut Pasteur, Paris France, 3Institut Pasteur, France
Folliculogenesis is a central process for female fertility that depends on mutual interactions between oocyte and somatic cells. Here, we report the striking reproductive features of a novel mouse model of premature ovarian failure. We generated mice with oocyte-specific inactivation (ocKO) of Omcg1/Zfp830 encoding a nuclear zinc finger protein involved in co-transcriptional processes and maintenance of genome integrity. Omcg1-deficient oocytes were rapidly eliminated at the onset of follicular growth. This was associated with an overall reduction in oocyte transcription and an accumulation of DNA double-strand breaks. Treatment with the c-Abl inhibitor imatinib prevented oocyte death, emphasizing the involvement of the c-Abl/p63 pathway in damaged oocyte elimination. All adult Omcg1ocKO females displayed early folliculogenesis arrest and sterility. Importantly, despite such a phenotype, Omcg1ocKO females exhibited a normal onset of puberty and sexual receptivity. Detailed studies of Omcg1ocKO ovaries by in situ analyses and real-time RT-PCR revealed the dramatic structural and functional remodeling of their somatic component. Indeed, oocyte-depleted follicles reorganized into follicular nests with preovulatory features, as shown by a high aromatase (Cyp19a1) and LH receptor (Lhcgr) gene expression. Steroid hormone assays showed that in mutant females estrogen production was similar as in controls. Moreover, despite the absence of terminal follicular growth and luteal differentiation, some mutant females exhibited a regular 4-5 day estrus cycle, as evidenced by vaginal smears. Vaginal cyclicity was, however, not associated with estrus-induced changes in pituitary LH b-subunit (Lhb) or ovarian Cyp19a1 gene expression, thus questioning the reliability of vaginal smears to assess ovarian activity. Collectively, our findings demonstrate the key role of Omcg1 for oocyte survival. Furthermore, this original mouse model of early oocyte loss highlights an unsuspected maintenance of estrogen production due to the remodeling of oocyte-depleted follicles. This dramatic ovarian plasticity allows sexual receptivity and patterns of estrus cyclicity despite full sterility.

Nothing to Disclose: JC, SV, CJG, MI, NC, MH, PA, SM, MC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: ANR EarlyFoll
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