Dullard deficiency causes hemorrhage in the adult ovarian follicles
Dullard deficiency causes hemorrhage in the adult ovarian follicles
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DOI：
10.1111/gtc.12575
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发表时间：
2018-05-01
期刊：
影响因子：
2.1
通讯作者：
Noda, Masaki
中科院分区：
文献类型：
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作者：
Hayata, Tadayoshi;Chiga, Masahiko;Noda, Masaki
在哺乳动物中，卵泡至少部分受骨形态发生蛋白（BMP）家族成员的调节。Dullard（也称为Ctdnep 1）基因编码一种磷酸酶，通过灭活或降解BMP受体来抑制BMP信号传导。在这里，我们报告了Col 1a 1-Cre诱导的Dullard突变小鼠显示出血性卵巢囊肿，红细胞聚集在卵泡中，导致不孕。在卵巢的颗粒细胞和睾丸的支持细胞中发现了由Col 1a 1 2.3-kb启动子驱动的表达Cre的细胞及其后代。DullardmRNA定位于卵巢颗粒细胞。参与类固醇激素生成的基因包括Cyp 11 a1、Hsd 3b 1和星星减少，而Smad 6和Smad 7（BMP诱导的抑制性Smads）的表达在Dullard突变卵巢中上调。使用Rosa 26-CreER小鼠进行的他莫昔芬诱导的Dullard缺失在2周内也导致出血性卵巢囊肿，通过施用BMP受体激酶的化学抑制剂LDN-193189来挽救，这表明Dullard缺陷的卵泡中的出血可能是由BMP信号增加引起的。因此，我们的结论是，Dullard是必不可少的卵巢稳态至少部分通过抑制BMP信号。
In mammals, the ovarian follicles are regulated at least in part by bone morphogenetic protein (BMP) family members. Dullard (also known as Ctdnep1) gene encodes a phosphatase that suppresses BMP signaling by inactivating or degrading BMP receptors. Here we report that the Col1a1-Cre-induced Dullard mutant mice displayed hemorrhagic ovarian cysts, with red blood cells accumulated in the follicles, resulting in infertility. Cells expressing Cre driven by Col1a1 2.3-kb promoter and their descendants were found in granulosa cells in the ovary and in Sertoli cells in the testis. DullardmRNA was localized to granulosa cells in the ovary. Genes involved in steroid hormone genesis including Cyp11a1, Hsd3b1 and Star were reduced, whereas expression of Smad6 and Smad7, BMP-inducible inhibitory Smads, was up-regulated in the Dullard mutant ovaries. Tamoxifen-inducible Dullard deletion in the whole body using Rosa26-CreER mice also resulted in hemorrhagic ovarian cysts in 2weeks, which was rescued by administration of LDN-193189, a chemical inhibitor of BMP receptor kinase, suggesting that the hemorrhage in the Dullard-deficient ovarian follicles might be caused by increased BMP signaling. Thus, we conclude that Dullard is essential for ovarian homeostasis at least in part via suppression of BMP signaling.