Apoptosis in recombination-deficient meiocytes

描述（由申请方提供）：在第一次减数分裂期间，需要减数分裂重组以对齐同源染色体进行分离。减数分裂母细胞监测减数分裂中的关键步骤，并且缺陷进展导致诱导程序性细胞死亡的减数分裂检查点的激活。最近的研究已经确定了在正常发育过程中以及在对细胞毒性损伤的反应中控制生殖系中的程序性细胞死亡的元件。但是对于减数分裂染色体代谢错误引起的细胞凋亡的遗传调控知之甚少。初步的工作表明，性母细胞有两个DMA损伤依赖性和非依赖性的减数分裂检查点。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。本研究的主要目的是：1）确定精子发生和卵子发生过程中减数分裂重组错误激活了哪些凋亡信号级联; 2）从遗传学上测试重组是否需要特定的促凋亡途径基因-缺陷性母细胞死亡，并确定观察到的细胞周期反应中的性二型性是否是这些差异使用的结果。基因.

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.