HORMAD2 is essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity
HORMAD2 is essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity
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DOI：
10.1111/gtc.12005
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发表时间：
2012-11-01
期刊：
影响因子：
2.1
通讯作者：
Kurahashi, Hiroki
中科院分区：
文献类型：
--
作者：
Kogo, Hiroshi;Tsutsumi, Makiko;Kurahashi, Hiroki
在减数分裂前期，染色体分离需要同源配对、联会和交换重组。检查点激酶ATR已被提出参与这些过程的质量监测，尽管其潜在机制在很大程度上仍然未知。在我们目前的研究中，我们产生了缺乏HORMAD 2的小鼠，HORMAD 2是一种定位于未突触减数分裂染色体的蛋白质。我们发现，这种Hormad 2缺陷阻碍了ATR活动的适当招聘到未突触的染色体。雄性Hormad 2缺陷小鼠由于性小体形成特征性损伤导致精母细胞损失而不育;形成ATR和γ H2 AX富集的抑制性染色质结构域，但部分与延长的性染色体轴分离。与雄性相反，缺乏Hormad 2的雌性是能生育的。然而，我们对Hormad 2/Spo 11双突变雌性的分析表明，卵母细胞数量与假性体形成的频率呈负相关，且呈Hormad 2基因剂量依赖性。这一结果表明，Spo 11缺陷的突触卵母细胞的消除与HORMAD 2依赖性伪体节的形成，这可能是由局部浓度的ATR活性在没有双链断裂启动。因此，我们的研究结果表明，HORMAD 2依赖的质量控制机制，承认unsynapsis和招聘ATR活动在哺乳动物减数分裂。
Meiotic chromosome segregation requires homologous pairing, synapsis and crossover recombination during meiotic prophase. The checkpoint kinase ATR has been proposed to be involved in the quality surveillance of these processes, although the underlying mechanisms remain largely unknown. In our present study, we generated mice lacking HORMAD2, a protein that localizes to unsynapsed meiotic chromosomes. We show that this Hormad2 deficiency hampers the proper recruitment of ATR activity to unsynapsed chromosomes. Male Hormad2-deficient mice are infertile due to spermatocyte loss as a result of characteristic impairment of sex body formation; an ATR- and gamma H2AX-enriched repressive chromatin domain is formed, but is partially dissociated from the elongated sex chromosome axes. In contrast to males, Hormad2-deficient females are fertile. However, our analysis of Hormad2/Spo11 double-mutant females shows that the oocyte number is negatively correlated with the frequency of pseudosex body formation in a Hormad2 gene dosage-dependent manner. This result suggests that the elimination of Spo11-deficient asynaptic oocytes is associated with the HORMAD2-dependent pseudosex body formation that is likely initiated by local concentration of ATR activity in the absence of double-strand breaks. Our results thus show a HORMAD2-dependent quality control mechanism that recognizes unsynapsis and recruits ATR activity during mammalian meiosis.