Highlights
- •Touch end-organ morphogenesis occurs post-natally and is instructed by the skin
- •Neurons innervating both glabrous and hairy skin form skin-type-appropriate endings
- •BMP5 and BMP7 are enriched in glabrous skin at developmentally critical time points
- •Formation of Meissner corpuscles is dependent on BMP receptor signaling
Summary
Mechanosensory neurons innervating the skin underlie our sense of touch. Fast-conducting, rapidly adapting mechanoreceptors innervating glabrous (non-hairy) skin form Meissner corpuscles, while in hairy skin, they associate with hair follicles, forming longitudinal lanceolate endings. How mechanoreceptors develop axonal endings appropriate for their skin targets is unknown. We report that mechanoreceptor morphologies across different skin regions are indistinguishable during early development but diverge post-natally, in parallel with skin maturation. Neurons terminating along the glabrous and hairy skin border exhibit hybrid morphologies, forming both Meissner corpuscles and lanceolate endings. Additionally, molecular profiles of neonatal glabrous and hairy skin-innervating neurons largely overlap. In mouse mutants with ectopic glabrous skin, mechanosensory neurons form end-organs appropriate for the altered skin type. Finally, BMP5 and BMP7 are enriched in glabrous skin, and signaling through type I bone morphogenetic protein (BMP) receptors in neurons is critical for Meissner corpuscle morphology. Thus, mechanoreceptor morphogenesis is flexibly instructed by target tissues.
Introduction
Our sense of touch allows us to identify and manipulate objects, communicate in social contexts, and detect and distinguish innocuous and harmful stimuli acting on the body. The first step leading to perception of, and reaction to, the heterogeneous repertoire of our tactile world is activation of touch sensory neurons, called mechanoreceptors, which have cell bodies residing in dorsal root ganglia (DRG) and trigeminal ganglia and form axonal endings in the skin.1 The mechanoreceptors that detect light touch are the low-threshold mechanoreceptors (LTMRs). These neurons are morphologically and physiologically diverse, with subtypes responding to different mechanical stimuli, including gentle indentation of the skin, hair deflection, movement across the skin, and vibration.2 Dysfunction of mechanoreceptors and their central circuits can lead to impaired sensation associated with neuropathies such as Charcot-Marie-Tooth disease, mechanical allodynia in neuropathic pain states, and hyperreactivity in certain developmental disorders.3,4,5,6 Despite the critical importance of touch, the mechanisms of development and acquisition of morphological specializations of the cutaneous tactile sensors remain incompletely understood.7
Soon after neuronal commitment to different lineages, newborn DRG sensory neurons extend axons through a range of intermediate targets and into their final target tissues.7 A key distinction between mechanosensory neurons arises from the skin target they innervate. In the mouse, glabrous (non-hairy) skin is localized to the ventral surface of the paws, whereas hairy skin is found across the body, including the trunk, tail, limbs, and dorsal surface of the paws. The cell bodies of hairy and glabrous-skin-innervating LTMRs intermingle within limb-level (C5–C8 and L3–L5) DRGs8 but their axonal specializations in the skin, called end-organs, differ according to the skin type they innervate. Present across mammalian species and sharing morphological and physiological properties,9,10,11,12 the end-organs endow LTMR subtypes with the ability to extract salient features of external stimuli, including indentation, vibration, and movement across the skin.1,13 Physiologically, LTMRs are classified based on their conduction velocity as Aβ, Aδ, and C, for rapid, intermediate, and slow conducting neurons, respectively, and according to their adaptation rate to skin indentation as rapidly adapting (RA), intermediate adapting (IA) or slowly adapting (SA).2,14,15
The different morphological features of glabrous and hairy skin LTMRs raise a fascinating and largely unexplored question: how is LTMR end-organ diversity achieved across different skin types? One possibility is that glabrous and hairy skin-innervating neurons are pre-determined to form the distinct end-organs associated with the different skin types. Alternatively, the properties of LTMRs may be unspecified during early development, and glabrous and hairy skin may differentially instruct morphogenesis of their axon terminals, thus endowing them with characteristic end-organ structures and physiological response properties. The latter possibility is appealing because it would allow nascent mechanosensory neurons to flexibly acquire features relevant to the skin type they innervate.
Here, we sought to determine when and how the distinct morphological features of glabrous and hairy-skin-innervating LTMRs arise over development and begin to define molecular mechanisms underlying this process. We focused on Meissner corpuscle-innervating and lanceolate ending-forming LTMRs of glabrous skin and hairy skin, respectively, because, despite having common genetic labeling strategies in mice, their end-organ structures are strikingly distinct (Figures 1A and 1B, left).16,17 In glabrous skin, Aβ LTMRs that express the neurotrophic factor receptors TrkB or Ret form Meissner corpuscles, which are end-organs nestled within dermal papillae. These Meissner corpuscle LTMRs detect light forces impinging on the skin as well as low-frequency vibrations.18,19,20,21 On the other hand, in hairy skin, both Ret+ Aβ RA-LTMRs and TrkB+ Aδ-LTMRs form longitudinal lanceolate endings, which wrap around hair follicles, rendering them sensitive to hair deflection as well as indentation of the nearby skin.17,19,22,23 Using anatomical, transcriptional, and mouse genetic approaches, we found that nascent Ret+ and TrkB+ mechanosensory neurons are not pre-determined to form a particular end-organ, rather these neurons can form either Meissner corpuscles or lanceolate endings depending on the skin type they innervate. Therefore, glabrous skin and hairy skin differentially instruct the morphological properties of nascent LTMRs. We also found that a glabrous-skin-specific bone morphogenetic protein (BMP) type I receptor signaling pathway shapes the architecture of Meissner corpuscles but not hairy skin lanceolate endings. Our findings support a model in which skin-type-specific secreted cues instruct LTMR end-organ formation and thus their unique morphological and physiological response properties and functions….
