The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance
The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance
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DOI：
10.1242/dev.00969
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发表时间：
2004-02-01
期刊：
影响因子：
4.6
通讯作者：
Treier, M
中科院分区：
文献类型：
--
作者：
Schmidt, D;Ovitt, CE;Treier, M
人类小睑裂/上睑下垂/内眦赘皮综合征（BPES）I型是一种常染色体显性遗传疾病，与卵巢早衰（POF）相关，由FOXL 2（翼螺旋/叉头结构域转录因子）突变引起。尽管已经表明FOXL 2在成年卵巢中表达，但其在卵泡发生中的功能尚不清楚。在这里，我们表明，小鼠Foxl 2基因是必不可少的颗粒细胞分化和卵巢维护。在Foxl 2（lacz）纯合子突变卵巢中，颗粒细胞不能完成鳞状向立方的转变，导致次级卵泡的缺失和卵母细胞闭锁。我们进一步证明，激活素β A和抗苗勒管抑制激素的表达是不存在或强烈减少Foxl 2（lacZ）纯合子突变卵巢。出乎意料的是，出生后两周，大多数（如果不是所有的话）卵母细胞表达Gdf 9在Foxl 2（lacz）纯合突变卵巢，表明几乎所有的原始卵泡已经开始在这个阶段的卵泡发生。在功能性颗粒细胞缺乏的情况下，这种激活导致卵母细胞闭锁和进行性卵泡耗竭。这些结果除了提供了BPES卵巢早衰的分子机制外，还表明颗粒细胞功能不仅对卵母细胞的生长至关重要，而且对维持体内卵泡静止也至关重要。
Human Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) type I is an autosomal dominant disorder associated with premature ovarian failure (POF) caused by mutations in FOXL2, a winged-helix/forkhead domain transcription factor. Although it has been shown that FOXL2 is expressed in adult ovaries, its function during folliculogenesis is not known. Here, we show that the murine Foxl2 gene is essential for granulosa cell differentiation and ovary maintenance. In Foxl2(lacz) homozygous mutant ovaries granulosa cells do not complete the squamous to cuboidal transition leading to the absence of secondary follicles and oocyte atresia. We further demonstrate that activin-betaA and anti-Mullerian inhibiting hormone expression is absent or strongly diminished in Foxl2(lacZ) homozygous mutant ovaries. Unexpectedly, two weeks after birth most if not all oocytes expressed Gdf9 in Foxl2(lacz) homozygous mutant ovaries, indicating that nearly all primordial follicles have already initiated folliculogenesis at this stage. This activation, in the absence of functional granulosa cells, leads to oocyte atresia and progressive follicular depletion. In addition to providing a molecular mechanism for premature ovarian failure in BPES, these results suggest that granulosa cell function is not only crucial for oocyte growth but also to maintain follicular quiescence in vivo.