A single-point mutation in TRPA1 drives heat resilience in oviparous embryos.

Abstract

The molecular basis for species-specific thermal adaptation in vertebrate sensory systems is not well understood. We show that a single-amino-acid change in the pore domain of ion channel transient receptor potential ankyrin 1 (TRPA1) during the synapsid-diapsid split rewired its heat sensitivity. Many oviparous vertebrates retaining the ancestral residue display TRPA1 heat activation, protecting embryonic development under high temperatures, whereas selection for an aspartate in mammals reduced thermal responsiveness. Blocking heat-activated TRPA1 in oviparous embryos impaired dorsal-root-ganglion axon growth, disrupted myelination, and caused limb weakness at hatching. Mechanistically, TRPA1-mediated Ca²⁺ influx triggers nuclear translocation of SP1, activating <i>CADM1</i> and <i>MDGA1</i>. Together, these results uncover an unexpected developmental role of TRPA1 in heat resilience, linking a single mutational event to embryonic survival under thermal stress and highlighting ion-channel evolution in adaptation.