HORMAD1-dependent checkpoint/surveillance mechanism eliminates asynaptic oocytes
HORMAD1-dependent checkpoint/surveillance mechanism eliminates asynaptic oocytes
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DOI：
10.1111/j.1365-2443.2012.01600.x
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发表时间：
2012-06-01
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
减数分裂粗线期检查点监测同源重组和联会的失败，以确保配子形成过程中染色体的分离。到目前为止，哺乳动物粗线期检查点的分子基础在很大程度上仍然未知。我们在这里报告说，小鼠HORMAD 1是所需的减数分裂前期检查点，消除联会卵母细胞。Hormad 1缺陷小鼠不育，并表现出广泛的同源配对和突触失败，与减数分裂HORMA结构域蛋白进化上保守的功能一致。出乎意料的是，Hormad 1缺陷卵巢含有正常数量的卵母细胞，尽管不联会，因此产生非整倍体卵母细胞，表明检查点失败。通过对Hormad 1/Spo 11双突变体的分析，发现Hormad 1缺陷消除了Spo 11缺陷卵巢中的大量卵母细胞损失。Hormad 1缺乏也会导致Spo 11缺乏的卵巢和睾丸中假性体的最终丧失。这些结果表明HORMAD 1参与了抑制性染色质结构域的形成，这在减数分裂前期检查点中是重要的。我们还发现，在Spo 11缺陷的睾丸和卵巢中，HORMAD 1广泛磷酸化，这表明新的DNA损伤独立的磷酸化信号转导参与了监测机制。我们目前的研究结果提供了线索，HORMAD 1依赖的检查点在哺乳动物减数分裂不联会的反应。
Meiotic pachytene checkpoints monitor the failure of homologous recombination and synapsis to ensure faithful chromosome segregation during gamete formation. To date, the molecular basis of the mammalian pachytene checkpoints has remained largely unknown. We here report that mouse HORMAD1 is required for a meiotic prophase checkpoint that eliminates asynaptic oocytes. Hormad1-deficient mice are infertile and show an extensive failure of homologous pairing and synapsis, consistent with the evolutionarily conserved function of meiotic HORMA domain proteins. Unexpectedly, Hormad1-deficient ovaries contain a normal number of oocytes despite asynapsis and consequently produce aneuploid oocytes, indicating a checkpoint failure. By the analysis of Hormad1/Spo11 double mutants, the Hormad1 deficiency was found to abrogate the massive oocyte loss in the Spo11-deficient ovary. The Hormad1 deficiency also causes the eventual loss of pseudo sex body in the Spo11-deficient ovary and testis. These results suggest the involvement of HORMAD1 in the repressive chromatin domain formation that is proposed to be important in the meiotic prophase checkpoints. We also show the extensive phosphorylation of HORMAD1 in the Spo11-deficient testis and ovary, suggesting an involvement of novel DNA damageindependent phosphorylation signaling in the surveillance mechanism. Our present results provide clues to HORMAD1-dependent checkpoint in response to asynapsis in mammalian meiosis.