Pomaville, M. B. | bioRxiv Science

bioRxiv2022

Follicle-innervating Aδ-low threshold mechanoreceptors organize through a population-dependent mechanism

The mammalian somatosensory system is comprised of multiple neuronal populations that form specialized, highly organized sensory endings in the skin. The organization of somatosensory endings is essential to their functions, yet the mechanisms which regulate this organization remain unclear. Using a combination of genetic and molecular labeling approaches, we examined the development of mouse hair follicle-innervating low-threshold mechanoreceptors (LTMRs) and explored competition for innervation targets as a mechanism involved in the patterning of their receptive fields. We show that follicle innervating neurons are present in the skin at birth and that LTMR receptive fields gradually add follicle-innervating endings during the first two postnatal weeks. Using a constitutive Bax knockout to increase the number of neurons in adult animals, we show that two LTMR subtypes have differential responses to an increase in neuronal population size: A{delta}-LTMR neurons shrink their receptive fields to accommodate the increased number of neurons innervating the skin, while C-LTMR neurons do not. Our findings suggest that competition for hair follicles to innervate plays a role in the patterning and organization of follicle-innervating LTMR neurons. Summary StatementA{delta} follicle-innervating low-threshold mechanoreceptor neurons form tiled receptive fields through competition for hair follicles during the early postnatal period.

neuroscience↗

bioRxiv2021

c-Kit mediates cutaneous sensory axon innervation and multi-kinase inhibitor-induced neurotoxicity

Peripheral somatosensory neurons innervate the skin and sense the environment. Loss of skin innervation, often caused by the "dying back" of distal somatosensory axons, is a common side effect of drug-induced peripheral neuropathies (DIPNs) and results in pain and sensory dysfunction. Targeted cancer therapies frequently employ multi-kinase inhibitor (MKI) drugs that each block multiple receptor tyrosine kinases. Many MKIs produce DIPNs but the molecular targets and cellular mechanisms underlying these are unknown. We performed live-imaging of cutaneous somatosensory axons in larval zebrafish during treatment with several MKIs known to induce DIPNs, and observed axonal retraction consistent with a dying back pathology. These results were replicated in mouse somatosensory neurons. Genetic knockout of potential MKI targets identified c-Kit receptor as a regulator of sensory axon innervation and a major target of these MKIs mediating loss of axonal density. In both fish and mammals, Kit receptor is expressed in cutaneous somatosensory neurons and its ligand, Kitlg, is expressed in the skin. Mosaic misexpression of Kitlg in the skin induced dramatic increases in local sensory axon density, suggesting an important role for Kit signaling in cutaneous axon growth and maintenance. Immunostaining and structure-function analysis revealed Src, a downstream Kit target, mediates Kits role in cutaneous axon innervation and MKI neurotoxicity. Our data shows that the Kit-Src signaling pathway has a major role in cutaneous sensory axon innervation and is a potential therapeutic target to address DIPNs caused by MKIs and other compounds.

neuroscience↗