Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice

Emanuele Pelosi (), Shakib Omari, Marc Michel, Jun Ding, Tomokazu Amano, Antonino Forabosco, David Schlessinger and Chris Ottolenghi
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Emanuele Pelosi: Laboratory of Genetics, NIA/NIH-IRP, 251 Bayview blvd, room 10B014, Baltimore, Maryland 21224, USA
Shakib Omari: Laboratory of Genetics, NIA/NIH-IRP, 251 Bayview blvd, room 10B014, Baltimore, Maryland 21224, USA
Marc Michel: Laboratory of Genetics, NIA/NIH-IRP, 251 Bayview blvd, room 10B014, Baltimore, Maryland 21224, USA
Jun Ding: Laboratory of Genetics, NIA/NIH-IRP, 251 Bayview blvd, room 10B014, Baltimore, Maryland 21224, USA
Tomokazu Amano: Laboratory of Genetics, NIA/NIH-IRP, 251 Bayview blvd, room 10B014, Baltimore, Maryland 21224, USA
Antonino Forabosco: Genomic Research Center, Cante di Montevecchio Association, via Negusanti
David Schlessinger: Laboratory of Genetics, NIA/NIH-IRP, 251 Bayview blvd, room 10B014, Baltimore, Maryland 21224, USA
Chris Ottolenghi: Unite’ UMR-S 747 Inserm–University of Paris Descartes, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des Saints Pères, 75270 Paris 06, France

Nature Communications, 2013, vol. 4, issue 1, 1-7

Abstract: Abstract During female reproductive life, ovarian follicle reserve is reduced by maturation and atresia until menopause ensues. Foxo3 is required to maintain the ovarian reserve in mice. Here we show that overexpression of constitutively active FOXO3 can increase ovarian reproductive capacity in mice. We find increased follicle numbers and decreased gonadotropin levels in aging FOXO3-transgenic mice compared with wild-type littermates, suggesting maintenance of a greater ovarian reserve. Based on cumulative progeny in aging animals, we find 31–49% increased fertility in transgenic females. The gene expression profile of Foxo3−/− knockout ovaries appears older than that of wild-type littermates, and the transgene induces a younger-looking profile, restoring much of the wild-type transcriptome. This is the first gain-of-function model of augmented reproductive reserve in mice, thus emphasizing the role of Foxo3 as a guardian of the ovarian follicle pool in mammals and a potential determinant of the onset of menopause.

Date: 2013
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DOI: 10.1038/ncomms2861

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