Behavioral genomics identifies Creld1 as a cross-modal regulator of somatosensation.

Somatosensation is mediated by dorsal root ganglion (DRG) neurons, which convert physical and chemical stimuli into electrical signals. However, the full repertoire of molecular components underlying somatosensation remains incompletely identified. Here we developed an efficient postnatal CRISPR-Cas9 knockout platform for interrogating DRG-expressed genes (such as Piezo2, Trpv1 and Scn9a) in mice using AAV9-mediated single-guide RNA delivery. Combining this approach with somatosensory behavioral assays, we performed a targeted screen of 20 genes and identified Creld1 as a cross-model regulator of somatosensation. Either single-guide RNA-mediated postnatal knockout or tamoxifen-induced Cre-mediated deletion of Creld1 in DRG neurons resulted in profound behavioral deficits in touch, temperature, pain and itch, whereas its overexpression enhanced touch and thermal responses. Mechanistically, CRELD1 functions as an auxiliary regulator of voltage-gated sodium channels (Nav) for controlling DRG neuron excitability. Together, this work establishes a robust postnatal screening platform for behavioral genomics and identifies Creld1 as a master regulator of somatosensory function.