Somatic regulation of germ cell apoptosis

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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.