GATA4 Deficiency Impairs Ovarian Function in Adult Mice
GATA4 Deficiency Impairs Ovarian Function in Adult Mice
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DOI：
10.1095/biolreprod.110.086850
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发表时间：
2011-05-01
影响因子：
3.6
通讯作者：
Wilson, David B.
中科院分区：
文献类型：
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作者：
Kyronlahti, Antti;Vetter, Melanie;Wilson, David B.
转录因子GATA4在颗粒细胞中表达，在较小程度上，在其他卵巢细胞类型中表达。对突变小鼠的研究表明，GATA4与其辅助因子ZFPM2（也称为FOG2）之间的相互作用是胎儿卵巢正常发育所必需的。然而，GATA4在出生后卵巢功能中的作用仍不清楚，部分原因是小鼠GATA4基因纯合突变的产前致命性。为了克服这一限制，我们研究了两种基因工程小鼠系的卵巢功能：C57BL/6 （B6）雌性小鼠杂合Gata4-null等位基因，和129；使用Cre-loxP重组系统和Amhr2-cre在增殖颗粒细胞中特异性删除Gata4的B6雌性小鼠。雌性B6 Gata4（+/-）小鼠青春期延迟，但发情周期长度和产仔数正常。与野生型小鼠相比，促性腺激素刺激的B6 Gata4（+/-）小鼠卵巢明显变小，释放的卵母细胞减少，产生的雌激素减少，推测的Gata4靶基因Star、Cyp11a1和Cyp19的mRNA表达减少。Gata4条件敲除（cKO）小鼠具有更严重的表型，包括生育力受损和卵巢囊肿变化。与Gata4（+/-）小鼠一样，促性腺激素刺激的cKO小鼠卵巢释放的卵母细胞较少，Cyp19的表达也低于对照小鼠。我们的发现，连同其他研究者的发现，支持了GATA4是胎儿和成年小鼠卵巢体细胞功能的关键转录调节因子的前提。
Transcription factor GATA4 is expressed in granulosa cells and, to a lesser extent, in other ovarian cell types. Studies of mutant mice have shown that interactions between GATA4 and its cofactor, ZFPM2 (also termed FOG2), are required for proper development of the fetal ovary. The role of GATA4 in postnatal ovarian function, however, has remained unclear, in part because of prenatal lethality of homozygous mutations in the Gata4 gene in mice. To circumvent this limitation, we studied ovarian function in two genetically engineered mouse lines: C57BL/6 (B6) female mice heterozygous for a Gata4-null allele, and 129; B6 female mice in which Gata4 is deleted specifically in proliferating granulosa cells using the Cre-loxP recombination system and Amhr2-cre. Female B6 Gata4(+/-) mice had delayed puberty but normal estrous cycle lengths and litter size. Compared to wild-type mice, the ovaries of gonadotropin-stimulated B6 Gata4(+/-) mice were significantly smaller, released fewer oocytes, produced less estrogen, and expressed less mRNA for the putative GATA4 target genes Star, Cyp11a1, and Cyp19. Gata4 conditional knockout (cKO) mice had a more severe phenotype, including impaired fertility and cystic ovarian changes. Like Gata4(+/-) mice, the ovaries of gonadotropin-stimulated cKO mice released fewer oocytes and expressed less Cyp19 than those of control mice. Our findings, coupled with those of other investigators, support the premise that GATA4 is a key transcriptional regulator of ovarian somatic cell function in both fetal and adult mice.