Apoptosis in recombination-deficient meiocytes

描述（由申请人提供）：在第一次减数分裂中，需要进行减数分裂重组，以使同源染色体对齐以进行分离。减数细胞监测减数分裂的关键步骤，缺陷的进展导致减数分裂检查点的激活，从而诱导程序性细胞死亡。最近的研究已经确定了在正常发育过程中控制生殖系程序性细胞死亡的因素以及对细胞毒性损伤的反应。但对减数分裂染色体代谢错误对细胞凋亡的遗传控制知之甚少。初步研究表明，减数细胞同时具有DMA损伤依赖性和独立减数分裂检查点。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。本提案中详细的工作旨在回答这些特定的目标：1)确定哪些凋亡信号级联是由于精子发生和卵子发生中的减数分裂重组错误而被激活的；2)从基因上检测重组缺陷减数细胞死亡是否需要特定的促凋亡途径基因，并确定在细胞周期反应中观察到的性别二态性是否是这些基因使用差异的结果。

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.