Comparative analysis of meiotic progression in female mice bearing mutations in genes of the DNA mismatch repair pathway
Comparative analysis of meiotic progression in female mice bearing mutations in genes of the DNA mismatch repair pathway
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DOI：
10.1095/biolreprod.107.065771
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发表时间：
2008-03-01
影响因子：
3.6
通讯作者：
Cohen, Paula E.
中科院分区：
文献类型：
--
作者：
Kan, Rui;Sun, Xianfei;Cohen, Paula E.
DNA错配修复（MMR）家族在多种情况下发挥作用，以保持大多数真核生物的基因组完整性。特别是，MMR家族的成员参与生殖细胞中减数分裂重组的过程。小鼠MMR基因突变导致减数分裂破坏在前期1，但这种破坏的程度往往不同的男性和女性的性母细胞。为了明确MMR蛋白在女性减数分裂中的作用，我们研究了MMR通路成员（Mlh 1、Mlh 3、Exo 1和Mlh 1的ATP酶缺陷变体Mlh 1（G67 R））缺失小鼠卵母细胞通过前期I和减数分裂的进展。MLH 1和MLH 3，参与新生交叉稳定的关键蛋白的共定位，是依赖于完整的异源二聚体的形成，并与卵母细胞的能力，通过中期II的进展是高度相关的。例外情况是Exo 1（-/-）卵母细胞，其中观察到正常MLH 1/MLH 3定位，随后未能进入中期II。所有的突变卵母细胞都能在胞核阻滞后恢复减数分裂，但它们显示出交叉的急剧下降（低于正常的25%），伴随着通过中期I的不同进展。两者合计，这些结果表明，MMR功能是必需的哺乳动物卵母细胞中的交叉的形成和稳定，在没有一个功能性的MMR系统，未能维持交叉的结果在一个降低的能力，通过正常进行的第一和第二次减数分裂分裂，尽管近正常水平的减数分裂恢复后，网状细胞逮捕。
The DNA mismatch repair (MMR) family functions in a variety of contexts to preserve genome integrity in most eukaryotes. In particular, members of the MMR family are involved in the process of meiotic recombination in germ cells. MMR gene mutations in mice result in meiotic disruption during prophase 1, but the extent of this disruption often differs between male and female meiocytes. To address the role of MMR proteins specifically in female meiosis, we explored the progression of oocytes through prophase I and the meiotic divisions in mice harboring deletions in members of the MMR pathway (Mlh1, Mlh3, Exo1, and an ATPase-deficient variant of Mlh1, Mlh1(G67R)). The colocalization of MLH1 and MLH3, key proteins involved in stabilization of nascent crossovers, was dependent on intact heterodimer formation and was highly correlated with the ability of oocytes to progress through to metaphase II. The exception was Exo1(-/-) oocytes, in which normal MLH1/MLH3 localization was observed followed by failure to proceed to metaphase II. All mutant oocytes were able to resume meiosis after dictyate arrest, but they showed a dramatic decline in chiasmata (to less than 25% of normal), accompanied by varied progression through metaphase I. Taken together, these results demonstrate that MMR function is required for the formation and stabilization of crossovers in mammalian oocytes and that, in the absence of a functional MMR system, the failure to maintain chiasmata results in a reduced ability to proceed normally through the first and second meiotic divisions, despite near-normal levels of meiotic resumption after dictyate arrest.