Apoptosis in recombination-deficient meiocytes

描述(申请人提供)：在第一次减数分裂中，需要进行减数分裂重组以对同源染色体进行分离。有丝分裂细胞监控减数分裂的关键步骤，有缺陷的减数分裂进程导致减数分裂检查点的激活，导致细胞程序性死亡。最近的研究已经确定了在生殖系正常发育过程中控制细胞程序性死亡的元件，以及对细胞毒性损伤的反应。但人们对染色体减数分裂代谢错误对细胞凋亡的遗传控制知之甚少。初步工作表明，小细胞既有依赖于DNA损伤的检查点，也有不依赖于减数分裂的检查点。有趣的是，这些检查点在精子发生和卵子发生过程中被不同地利用。这项建议中详细介绍的工作试图回答这些特定的目标：1)确定精子发生和卵子发生中的减数分裂重组错误导致哪些凋亡信号级联反应被激活；2)从遗传学角度测试重组缺陷的小细胞死亡是否需要特定的促凋亡途径基因，并确定所观察到的细胞周期反应中的性别二型性是否是这些基因不同使用的结果。

DESCRIPTION (provided by applicant): Meiotic recombination is required to align homologous chromosomes for segregation during the first meiotic division. Meiocytes monitor key steps in meiosis and defective progression results in activation of meiotic checkpoints that induce programmed cell death. Recent studies have identified elements that control programmed cell death in the germline during the course of normal development as well as in response to cytotoxic injury. But less is known about the genetic control of apoptosis in response to errors in meiotic chromosome metabolism. Preliminary work suggests that meiocytes have both DMA damage-dependent and -independent meiotic checkpoints. Intriguingly, these checkpoints are differentially utilized during spermatogenesis and oogenesis. The work detailed in this proposal seeks to answer these specific aims: 1) to determine which apoptotic signaling cascades are activated as a result of meiotic recombination errors in spermatogenesis and oogenesis; 2) to genetically test whether specific pro-apoptotic pathway genes are required for recombination-defective meiocyte cell death and to determine whether the observed sexual dimorphism in cell cycle responses is a consequence of differential use of these genes.