Somatic regulation of germ cell apoptosis

选择稳定的基因组进行遗传是繁育和物种保存的重要前提。对DNA损伤的凋亡反应是消除基因组受损生殖细胞的重要检查点机制。哺乳动物的配子发生是高度复杂的，而且在实验上更难获得。因此，我们研究了线虫配子发生过程中的DNA损伤反应。线虫和人类之间的DNA损伤反应和凋亡机制是高度保守的。我们先前已经证明，在减数分裂粗线期细胞中，保守的P53途径调节DNA损伤诱导的凋亡。我们最近的数据表明，在携带DNA双链断裂(DSB)的生殖细胞中，体细胞应激信号是诱导细胞凋亡所必需的。我们发现，PMK-1 MAPK是人类p38应激MAPK的同源基因，它在肠道细胞中特异地发挥非细胞自主调节生殖细胞凋亡的功能。此外，我们还证明了PMK-1/p38介导的肠道应激信号加剧了DNA损伤诱导的生殖细胞死亡，并影响了非整倍体的遗传性。因此，我们假设躯体应激监测会影响可遗传基因组的质量控制。在这项建议中，我们希望(1)探索肠道应激信号如何被激活以响应减数分裂DSB，(2)研究PMK-1诱导的多肽分泌影响生殖细胞凋亡的机制，(3)评估肠道应激信号如何影响减数分裂染色体分离，以及(4)确定影响生殖细胞凋亡的躯体应激因素。本建议旨在揭示新的调控机制，通过躯体应激监测影响DNA损伤诱导的生殖细胞凋亡，从而控制可遗传基因组的质量。鉴于DNA损伤反应和胁迫信号通路是高度保守的，我们认为这些结果对于理解体细胞对减数分裂质量控制的影响将是重要的，这可能会影响对人类生育和遗传的基本机制的理解。确定体细胞对配子发生的影响可能为解决人类不孕不育和非整倍体问题开辟新的途径。

The selection of stable genomes for inheritance is an important prerequisite for fertility and species preservation. The apoptotic response to DNA damage comprises an important checkpoint mechanism to eliminate genomically compromised germ cells. Mammalian gametogenesis is highly complex and experimentally less accessible. We, therefore, investigate the apoptotic DNA damage response during C. elegans gametogenesis. The DNA damage response and the apoptosis mechanisms are highly conserved between nematodes and human. We have previously shown that a conserved p53 pathway regulates DNA damage-induced apoptosis in meiotic pachytene cells. Our recent data establish that somatic stress signaling is required for the induction of apoptosis in the germ cells carrying DNA double strand breaks (DSBs). We show that the PMK-1 MAPK, which is the ortholog of the human p38 stress MAPK, specifically functions in the intestinal cells to non-cell-autonomously regulate germ cell apoptosis. Moreover, we demonstrate that PMK-1/p38-mediated intestinal stress signaling exacerbates DNA damage-induced germ cell death and impacts the heritability of aneuploidy. We, therefore, hypothesize that somatic stress surveillance influences the quality control of the heritable genome. In this proposal, we wish to (1) explore how intestinal stress signaling is activated in response to meiotic DSBs, (2) investigate the mechanisms through which secreted PMK-1-induced peptides impact germ cell apoptosis, (3) assess how intestinal stress signaling impact meiotic chromosome segregation, and (4) identify somatic stress factors that impact the germ cell apoptosis.This proposal aims to uncover novel regulatory mechanisms through which somatic stress surveillance impacts DNA damage-induced germ cell apoptosis and thus the quality control of heritable genomes. Given that the DNA damage response and stress signaling pathways are highly conserved, we suggest that these results will be important for understanding the somatic influence on meiotic quality control that might impact the understanding of fundamental mechanisms that underlie human fertility and inheritance. Determining somatic influences on gametogenesis might open new avenues for addressing infertility and aneuploidy in humans.