Cholinergic regulation of epidermal neurons

/Abstract Unlike CNS neurons, peripheral neurons routinely regrow axons after injury. Many factors promote neuronal survival and subsequent axonal re-growth, wayfinding and target contact and there has been considerable interest in enhancing these survival, support and growth mechanisms to promote successful reinnervation of tissue targets after physical injury and to prevent and/or reverse nerve degeneration during or following exposure to toxic or metabolic insults. Mechanisms restraining growth of neurons have been less extensively explored, although the actions of Nogo-A and semaphorins have been studied with interest in blocking their inhibition to facilitate recovery following neurological injury. We have accumulated data indicating that peripheral sensory neurons undergo constraint of growth via the GPCR muscarinic acetylcholine type 1 receptor (M1R) where the primary endogenous agonist is acetylcholine (ACh). Peripheral neurons express functional M1R and neurite outgrowth from sensory neurons in culture is suppressed by over-expression of M1R or by treatment with M1R agonists whereas growth is enhanced by selective and specific M1R antagonists. These data support a role for ACh in restraining sensory neuron growth but the source of ACh and its site of action in vivo remain unclear. Keratinocytes represent around 90% of cells in the epidermis of the skin. They bind together via tight junctions but rapid epidermal turnover (12-16 days) requires continuous migration of keratinocytes so that this barrier is dynamic. Coordination of this rapidly changing environment requires that keratinocytes communicate amongst themselves, which they do via release of a variety of factors and expression of associated receptors. One such mechanism involves the neurotransmitter ACh which acts on both nicotinic and muscarinic receptors expressed by adjacent keratinocytes to coordinate proliferation, growth, migration and melanin synthesis. As keratinocytes also form en passant synapses with sensory neurons in the epidermis, we now propose the hypothesis that keratinocyte derived ACh, acting via M1R, constrains excessive growth and arborization of sensory neurons in the skin. We will test this hypothesis by a combination of in vitro and in vivo studies that take advantage of our recent development of mice with inducible conditional knockdown of the ACh synthesizing enzyme choline acetyltransferase (ChAT) in keratinocytes. Project Number: 1R21NS146792-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: NIGEL CALCUTT | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $439,875 | Activity Code: R21 | Study Section: Neurodifferentiation, Plasticity, Regeneration and Rhythmicity Study Section[NDPR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11288423