Mouse behavioral genomics identifies Creld1 as a gatekeeper of somatosensation

Somatosensation enables the perception of touch, temperature, pain, and itch. These sensory modalities are mediated by primary sensory neurons in the dorsal root ganglion (DRG), which convert physical and chemical stimuli into electrical signals using specialized molecular sensors, including the touch sensor PIEZO2 (Ref1,2) and temperature sensors such as TRPV1 (Ref3,4), coupled with downstream voltage-gated sodium channels (Nav) like Nav1.7 (Ref5,6). However, the full repertoire of molecular components involved in somatosensory processing remains incompletely identified. Here, we developed an efficient postnatal CRISPR-Cas9 knockout platform to screen DRG-expressed genes via AAV9-sgRNA delivery. Combining this approach with behavioral assays of somatosensory responses, we validated the roles of PIEZO2 and TRPV1 in sensing gentle touch and noxious heat, respectively, and the broad involvement of Nav1.7 in distinct somatosensory modalities. Remarkably, a targeted screen of 20 DRG-expressed genes identified the Cysteine-rich with EGF-like domains 1 (Creld1) as a master regulator of somatosensation. Either sgRNA-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 perception, while its overexpression enhanced touch and thermal responses. Mechanistically, Creld1 functions as a novel auxiliary regulator of Nav for controlling the excitability of DRG neurons. The biochemical interaction and functional modulation of Nav by mouse Creld1 are mediated via its C-terminal transmembrane region. Notably, this domain is conserved in mouse Creld1 and some isoforms of human CRELD1, resulting in an isoform-dependent regulation of Nav1.7. Together, this work establishes a robust postnatal screening platform for somatosensory genomics and identifies Creld1 as a master regulator of somatosensory function, and provides novel therapeutic strategy for pain and itch treatment.