Mammalian oogonia proliferate without completing cytokinesis, forming cysts. Within these, oocytes differentiate and initiate meiosis, promoting double-strand break (DSBs) formation, which are repaired by homologous recombination (HR) causing the pairing and synapsis of the homologs. Errors in these processes activate checkpoint mechanisms, leading to apoptosis. At the end of prophase I, in contrast with what is observed in spermatocytes, oocytes accumulate unrepaired DSBs. Simultaneously to the cyst breakdown, there is a massive oocyte death, which has been proposed to be necessary to enable the individualization of the oocytes to form follicles. Based upon all the above-mentioned information, we hypothesize that the apparently inefficient HR occurring in the oocytes may be a requirement to first eliminate most of the oocytes and enable cyst breakdown and follicle formation. To test this idea, we compared perinatal ovaries from control and mutant mice for the effector kinase of the DNA Damage Response (DDR), CHK2. We found that CHK2 is required to eliminate ~50% of the fetal oocyte population. Nevertheless, the number of oocytes and follicles found in Chk2-mutant ovaries three days after birth was equivalent to that of the controls. These data revealed the existence of another mechanism capable of eliminating oocytes. In vitro inhibition of CHK1 rescued the oocyte number in Chk2^-/- mice, implying that CHK1 regulates postnatal oocyte death. Moreover, we found that CHK1 and CHK2 functions are required for the timely breakdown of the cyst and to form follicles. Thus, we uncovered a novel CHK1 function in regulating the oocyte population in mice. Based upon these data, we propose that the CHK1- and CHK2-dependent DDR controls the number of oocytes and is required to properly break down oocyte cysts and form follicles in mammals.

哺乳动物卵泡增殖而未完成胞质分裂，形成囊肿。在这些卵母细胞中，卵母细胞分化并开始减数分裂，促进双链断裂（DSBs）的形成，并通过同源重组（HR）进行修复，引起同源物的配对和突触。这些过程中的错误会激活检查点机制，从而导致凋亡。在前期I结束时，与在精母细胞中观察到的相反，卵母细胞会积聚未修复的DSB。在囊肿破裂的同时，存在大量的卵母细胞死亡，这被认为是使卵母细胞个体化以形成卵泡所必需的。根据上述所有信息，我们假设在卵母细胞中发生的明显低效的HR可能是首先消除大多数卵母细胞并使囊肿破裂和卵泡形成的必要条件。为了验证这一想法，我们比较了对照组和突变小鼠的围产期卵巢中DNA损伤反应（DDR）CHK2的效应激酶。我们发现需要CHK2才能消除〜50％的胎儿卵母细胞数量。然而，发现卵母细胞和卵泡的数量出生后三天的Chk2-突变卵巢与对照组相同。这些数据表明存在另一种能够消除卵母细胞的机制。体外抑制CHK1拯救了Chk2 ^-/-小鼠的卵母细胞数量，这表明CHK1调节产后卵母细胞的死亡。此外，我们发现需要CHK1和CHK2功能才能及时分解囊肿并形成卵泡。因此，我们发现了一种新的CHK1在调节小鼠卵母细胞中的功能。基于这些数据，我们建议依赖CHK1和CHK2的DDR控制卵母细胞的数量，并且需要适当地分解卵母细胞的囊肿并在哺乳动物中形成卵泡。