FZD1 Regulates Cumulus Expansion Genes and Is Required for Normal Female Fertility in Mice
FZD1 Regulates Cumulus Expansion Genes and Is Required for Normal Female Fertility in Mice
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DOI：
10.1095/biolreprod.112.102608
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发表时间：
2012-11-01
影响因子：
3.6
通讯作者：
Boerboom, Derek
中科院分区：
文献类型：
--
作者：
Lapointe, Evelyne;Boyer, Alexandre;Boerboom, Derek
WNT 4是小鼠正常卵泡发育和雌性生育力所必需的，但其信号如何转导仍不清楚。Fzd 1编码一种WNT受体，其表达在排卵前期的壁颗粒细胞和卵丘细胞中显著诱导，其方式与Wnt 4相似。为了研究FZD 1在卵巢生理学中的生理作用并确定它是否作为WNT 4的受体，通过基因靶向创建了Fzd 1缺失小鼠。尽管罕见的Fzd 1（-/-）雌性由于子宫纤维化和卵巢管基质增生而不育，但大多数雌性生育力低下，相对于对照组，平均每窝产生约1只幼仔。与WNT 4缺陷小鼠不同，Fzd 1（-/-）小鼠的卵巢重量、卵泡数量、类固醇激素产生和WNT 4靶基因表达水平正常。对排卵期卵泡颗粒细胞的微阵列分析显示，Fzd 1（-/-）小鼠中很少有基因的表达发生改变。然而，卵丘卵母细胞复合体（COCs）的基因表达分析显示，（Zp 3、Dppa 3、Nlrp 5和Bmp 15）和积云（Btc、Ptgs 2、Sema 3a、Ptx 3、Il 6、Nts、Alcam和Cspg 2）基因对排卵信号的调节，而这些基因的表达在来自Wnt 4的WNT 4缺陷型COCs中没有改变。（tm1.1Boer/tm1.1Boer）; Tg（CYP 19 A1-cre）1 Jri小鼠。尽管基因表达改变，但在体外和体内Fzd 1（-/-）COCs中，卵丘扩张似乎正常。总之，这些结果表明，Fzd 1是正常女性生育力所必需的，并可能部分调节卵母细胞成熟和卵丘细胞功能，但它不太可能作为唯一的卵巢WNT 4受体发挥作用。
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 approximate to 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 cumulusoocyte 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.