title: Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice.
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.
authors.affiliation: Laboratory of Genetics, NIA/NIH-IRP, 251 Bayview blvd, room 10B014, Baltimore, Maryland 21224, USA. pelosie@mail.nih.gov
authors.forename: Emanuele
authors.initials: E
authors.lastname: Pelosi
authors.forename: Shakib
authors.initials: S
authors.lastname: Omari
authors.forename: Marc
authors.initials: M
authors.lastname: Michel
authors.forename: Jun
authors.initials: J
authors.lastname: Ding
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Amano
authors.forename: Antonino
authors.initials: A
authors.lastname: Forabosco
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
mesh_terms: D000818:Animals; D005260:Female; D005298:Fertility; D005640:Follicle Stimulating Hormone / Q000097:blood; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D009865:Oocytes / Q000166:cytology / Q000378:metabolism*; D006080:Ovarian Follicle / Q000254:growth & development / Q000378:metabolism; D010053:Ovary / Q000166:cytology / Q000378:metabolism*; D019076:Transgenes
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone