title: FZD1 regulates cumulus expansion genes and is required for normal female fertility in mice.
abstract: WNT4 is required for normal ovarian follicle development and female fertility in mice, but how its signal is transduced remains unknown. Fzd1 encodes a WNT receptor whose expression is markedly induced in both mural granulosa cells and cumulus cells during the preovulatory period, in a manner similar to Wnt4. To study the physiological roles of FZD1 in ovarian physiology and to determine whether it serves as receptor for WNT4, Fzd1-null mice were created by gene targeting. Whereas rare Fzd1(-/-) females were sterile because of uterine fibrosis and ovarian tubulostromal hyperplasia, most were subfertile, producing ≈1 fewer pup per litter on average relative to controls. Unlike WNT4-deficient mice, ovaries from Fzd1(-/-) mice had normal weights, numbers of follicles, steroid hormone production, and WNT4 target gene expression levels. Microarray analyses of granulosa cells from periovulatory follicles revealed few genes whose expression was altered in Fzd1(-/-) mice. However, gene expression analyses of cumulus-oocyte complexes (COCs) revealed a blunted response of both oocyte (Zp3, Dppa3, Nlrp5, and Bmp15) and cumulus (Btc, Ptgs2, Sema3a, Ptx3, Il6, Nts, Alcam, and Cspg2) genes to the ovulatory signal, whereas the expression of these genes was not altered in WNT4-deficient COCs from Wnt4(tm1.1Boer/tm1.1Boer);Tg (CYP19A1-cre)1Jri mice. Despite altered gene expression, cumulus expansion appeared normal in Fzd1(-/-) COCs both in vitro and in vivo. Together, these results indicate that Fzd1 is required for normal female fertility and may act in part to regulate oocyte maturation and cumulus cell function, but it is unlikely to function as the sole ovarian WNT4 receptor.
authors.affiliation: Centre de Recherche en Reproduction Animale, Université de Montréal, Saint-Hyacinthe, Québec, Canada.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lapointe
authors.forename: Alexandre
authors.initials: A
authors.lastname: Boyer
authors.forename: Charlène
authors.initials: C
authors.lastname: Rico
authors.forename: Marilène
authors.initials: M
authors.lastname: Paquet
authors.forename: Heather L
authors.initials: HL
authors.lastname: Franco
authors.forename: Jan
authors.initials: J
authors.lastname: Gossen
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: JoAnne S
authors.initials: JS
authors.lastname: Richards
authors.forename: Derek
authors.initials: D
authors.lastname: Boerboom
mesh_terms: D000818:Animals; D054885:Cumulus Cells / Q000502:physiology*; D005260:Female; D005298:Fertility / Q000502:physiology*; D051157:Frizzled Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000502:physiology*; D006107:Granulosa Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D006080:Ovarian Follicle / Q000254:growth & development; D010053:Ovary / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: D051157:Frizzled Receptors; C489739:Fzd1 protein, mouse