Sensory neurons safeguard from mutational inheritance by controlling the CEP-1/p53-mediated DNA damage response in primordial germ cells

The genome integrity control in primordial germ cells (PGCs) is prerequisite for the inheritance of stable genomes. The PGCs in C. elegans are embedded in a somatic niche that regulates its DNA damage response (DDR). Here, we show that the AMPK-like kinases KIN-29 and AAK-2 are required for arresting PGCs carrying persistent DNA damage. We determined that the ASI neurons, which sense environmental conditions such as nutrient availability, secrete the TGF-beta-like ligand DAF-7 that is recognized by the DAF-1 receptor in PGCs. ASI-dependent DAF-7 signaling regulates the induction of CEP-1/p53 in the PGCs amid persistent DNA damage. Using single worm whole genome sequencing, we establish that defective ASI control of the CEP-1/p53-regulated DDR in PGCs ultimately results in the inheritance of de novo germline mutations. Our results indicate that sensory neurons safeguard from the inheritance of germline mutations suggesting the possibility that perception of the environment could direct genetic inheritance. One sentence summary The ASI sensory neurons regulate the CEP-1/p53-dependent DNA damage response of primordial germ cells via TGF-beta signaling and influence inherited mutational burden.