A role for axon-glial interactions and Netrin-G1 signaling in the formation of low-threshold mechanoreceptor end organs

Low-threshold mechanoreceptors (LTMRs) and their cutaneous end organs convert light mechanical forces acting on the skin into electrical signals that propagate to the central nervous system. In mouse hairy skin, hair follicle-associated longitudinal lanceolate complexes, which are end organs comprising LTMR axonal endings that intimately associate with terminal Schwann cell (TSC) processes, mediate LTMR responses to hair deflection and skin indentation. Here, we characterized developmental steps leading to the formation of A beta rapidly adapting (RA)- LTMR and AdLTMR lanceolate complexes. During early postnatal development, A beta RA-LTMRs and Ad-LTMRs extend and prune cutaneous axonal branches in close association with nascent TSC processes. Netrin-G1 is expressed in these developing A beta RA-LTMR and Ad-LTMR lanceolate endings, and Ntng1 ablation experiments indicate that Netrin-G1 functions in sensory neurons to promote lanceolate ending elaboration around hair follicles. The Netrin-G ligand (NGL-1), encoded by Lrrc4c, is expressed in TSCs, and ablation of Lrrc4c partially phenocopied the lanceolate complex deficits observed in Ntng1 mutants. Moreover, NGL-1-Netrin-G1 signaling is a general mediator of LTMR end organ formation across diverse tissue types demonstrated by the fact that A beta RA-LTMR endings associated with Meissner corpuscles and Pacinian corpuscles are also compromised in the Ntng1 and Lrrc4c mutant mice. Thus, axon-glia interactions, mediated in part by NGL-1-Netrin-G1 signaling, promote LTMR end organ formation.

Automated summary

This study characterizes the developmental steps leading to the formation of A beta rapidly adapting (RA)-LTMR and AdLTMR lanceolate complexes, and reveals the crucial roles of Netrin-G1 and NGL-1-Netrin-G1 signaling in promoting LTMR end organ formation. The findings demonstrate the importance of axon-glia interactions in this process and have implications for understanding sensory perception.