FZD1 Regulates Cumulus Expansion Genes and Is Required for Normal Female Fertility in Mice1

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.

The Wnt/JNK signaling target gene alcam is required for embryonic kidney development

“…At the molecular level, we found alcam to be regulated by Fzd3 signaling. Our data strongly support earlier findings (Gessert et al, 2008;Lapointe et al, 2012;Prieve and Moon, 2003), demonstrating that alcam is a direct target gene of β-Cateninindependent Wnt signaling at the transcriptional level. Therefore, we can add alcam to the currently very short list of two direct target genes of β-Catenin-independent Wnt signaling in vertebrates: eaf2 (Maurus et al, 2005) and pcdh8 (Schambony and Wedlich, 2007).…”

“…However, analyses regarding a potential function of Alcam during pronephros development are not yet available. In addition, earlier experiments suggested that alcam is regulated by non-canonical Wnt signaling (Gessert et al, 2008;Lapointe et al, 2012;Prieve and Moon, 2003). It remained elusive how alcam is regulated by β-Catenin-independent Wnt signaling and whether alcam is involved in Wnt mediated aspects of nephrogenesis.…”

Temporal and spatial expression profiles of Frizzled 3 in the ovary during the estrous cycle

“…Our results indicate that the Wnt signaling pathway is vital to regulating follicular development in the ovary. So far, studies have showed that Frizzled 1 and Frizzled 2 are found in different parts of the rodent ovary (Chan et al, 1992;Wang et al, 2010b;Lapointe et al, 2012). Interestingly, in human cumulus cells, Frizzled 3 can bind to Wnt 2, but it is not known which downstream signaling pathways are activated following this interaction (Wang et al, 2009).…”

“…Recently, Wnt signaling has been implicated in ovarian development, oogenesis, and early embryonic development (Chan et al, 1992;Vainio et al, 1999;Ricken et al, 2002;Boerboom et al, 2005;Hsieh et al, 2002Hsieh et al, , 2005Kimura et al, 2006;Wu et al, 2007;Wang et al, 2009Wang et al, , 2010bLapointe et al, 2012). Vainio et al (1999) found that Wnt 4-deficient mice exhibit sex reversal and a paucity of oocytes in the newborn ovary, while mice null for Frizzled 4 are infertile and exhibit impaired function of the corpus luteum .…”

“…Co-immunoprecipitation experiments have shown that Wnt 2 can interact with Frizzled 3 in human cumulus cells (Lapointe et al, 2012) but very little is known about the expression pattern or function of Frizzled 3 in the mouse ovary. Therefore, the aim of this study was to explore the spatial and temporal expression profiles of Frizzled 3 mRNA and protein in the mouse ovary during the estrous cycle.…”