Abstract
Merkel cell-neurite complexes are specialized mechanosensory end organs that mediate discriminative touch sensation. It is well established that type I slowly adapting (SAI) mechanoreceptors, which express neural filament heavy chain (NFH), innervate Merkel cells. It was previously shown that neurotrophic factor NT3 and its receptor TrkC play crucial roles in controlling touch dome Merkel cell innervation of NFH+ fibers. In addition, nerve fibers expressing another neurotrophic tyrosine receptor kinase (NTRK), Ret, innervate touch dome Merkel cells as well. However, the relationship between afferents responsive to NT3/TrkC signaling and those expressing Ret is unclear. It is also controversial if these Ret+ fibers belong to the early or late Ret+ DRG neurons, which are defined based on the co-expression and developmental dependence of TrkA. To address these questions, we genetically traced Ret+ and TrkC+ fibers and analyzed their developmental dependence on TrkA. We found that Merkel cells in neonatal mouse touch domes receive innervation of two types of fibers: one group is Ret+, while the other subset expresses TrkC and NFH. In addition, Ret+ fibers depend on TrkA for their survival and normal innervation whereas NFH+ Merkel cell innervating fibers are almost unaltered in TrkA mutant mice, supporting that Ret+ and NFH+/TrkC+ afferents are two distinct groups. Ret signaling, on the other hand, plays a minor role for the innervation of neonatal touch domes. In contrast, Merkel cells in the glabrous skin are mainly contacted by NFH+/TrkC+ afferents. Taken together, our results suggest that neonatal Merkel cells around hair follicles receive dual innervation while Merkel cells in the glabrous skin are mainly innervated by only SAI mechanoreceptors. In addition, our results suggest that neonatal Ret+ Merkel cell innervating fibers most likely belong to the late but not early Ret+ DRG neurons.
Highlights
Touch sensation, which is mediated by primary mechanosensory neurons, is critical for our daily life and social interactions
We found that Merkel cells in the mouse back hairy skin are innervated by two different types of fibers
We examined Merkel cell innervation in the P0 back hairy skin using antibodies against cytokeratin 8 (CK8), green fluorescent protein (GFP), and neural filament heavy chain (NFH)
Summary
Touch sensation, which is mediated by primary mechanosensory neurons, is critical for our daily life and social interactions. One main type of mechanosensory neurons is the Ab low-threshold mechanoreceptors (Ab LTMR) [1,2,3], which are large-diameter, NFH+, have highly myelinated axons, and innervate morphologically specialized mechanosensory end organs. Ab LTMR can be further divided into either rapidly adapting (RA) or slowly adapting (SA) mechanoreceptors based on their adaptation properties to sustained mechanical stimuli [4]. The Merkel cell-neurite complex is one of the best known types of mechanosensory end organs [2,5,6]. Since afferents displaying type I SA mechanoreceptor properties (SAI) usually innervate skin regions that are enriched with Merkel cells [5,8], it is well accepted that the Merkel cell-neurite complexes are the ‘‘SAI’’ mechanoreceptors
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