Dissection of Merkel cell formation in hairy and glabrous skin reveals a common requirement for FGFR2‐mediated signalling

Abstract

Merkel cells are mechanosensory cells involved in tactile discrimination. Merkel cells have been primarily studied in the murine back skin, where they are found in specialized structures called touch domes located around primary hair follicles. Yet, little is known about the morphogenesis of Merkel cells in areas of the skin devoid of hair, such as the glabrous paw skin. Here, we describe Merkel cell formation in the glabrous paw skin during embryogenesis. We first found in the glabrous paw skin that Merkel cells were specified at E15.5, 24 hours later, compared to in the back skin. Additionally, by performing lineage‐tracing experiments, we found that unlike in the back skin, SOX9(+) cells do not give rise to Merkel cells in the glabrous paw skin. Finally, we compared the transcriptomes of Merkel cells in the back and the glabrous paw skin and showed that they are similar. Genetic and transcriptome studies showed that the formation of Merkel cells in both regions was controlled by similar regulators. Among them was FGFR2, an upstream factor of MAPK signalling that was reported to have a critical function in Merkel cell formation in the back skin. Here, we showed that FGFR2 is also required for Merkel cell development in the glabrous paw skin. Taken together, our results demonstrate that Merkel cells in the murine back skin and glabrous paw skin are similar, and even though their formation is controlled by a common genetic programme, their precursor cells might differ.

Conversion of Sox2-dependent Merkel cell carcinoma to a differentiated neuron-like phenotype by T antigen inhibition

“…In the DE analysis, we also investigated MCC marker genes (34–37) and Merkel cell marker genes, which have been previously characterized in Atoh1 + mouse Merkel cells as compared to Atoh1 − epidermal cells (16, 17). Atoh1 is the Merkel cell lineage-determining transcription factor, which is essential for Merkel cell development in mouse skin (18, 38).…”

“…MCC are neuroendocrine tumors with morphologic and immunophenotypic similarities to Merkel cells (15). Transcriptional profiling of the Merkel cells in mouse skin showed that these cells express neuronal transcription factors, presynaptic molecules, and ion-channel subunits (16, 17). Of them, Atoh1 and Sox2 are critical transcription factors for Merkel cell development, in which Atoh1 plays a role in Merkel cell specification, while Sox2 controls Merkel cell maturation (18–21).…”

Keratinocytes Communicate with Sensory Neurons via Synaptic‐like Contacts

“…8,[10][11][12]18 Because keratinocytes have an ectodermal origin, similar to the nervous system, and descend from epidermal stem cells that also give rise to Merkel cells, 19,20 we hypothesized that epidermal keratinocytes could communicate with sensory neurons via chemical synaptic structures, 21 similar to Merkel cells. [22][23][24][25] As a central thread, we referred to the classical definition of a chemical synapse: (1) a specialized contact area that allows the passage of information between two cells, at least one of the cells being a neuron; (2) 3 regions, including a presynaptic region that contains synaptic vesicles; (3) vesicles that release neurotransmitter(s) through exocytosis in a narrow gap called the synaptic cleft; and (4) the neurotransmitters bind to specific receptors in the postsynaptic region to transmit information. By assessing these criteria, contacts were explored by morphological, molecular, and functional approaches in cocultures of epidermal keratinocytes and sensory neurons.…”

Understanding skin morphogenesis across developmental, regenerative and evolutionary levels

“…Not surprisingly, research on skin morphogenesis benefits from many classic as well as newly emerging experimental approaches. Genomic approaches, including single‐cell profiling, are becoming especially powerful new research tools, exemplified by the use of RNA‐sequencing in several papers in this issue . Intravital imaging provides a platform to observe cellular behaviours in real time .…”

“…The study by Wong's group reports on the role of GATA6 in regulating maintenance of the uppermost hair follicle compartment, while another study explores the role of FAM83G, a putative effector of WNT and BMP signalling pathways, in hair follicle morphogenesis, differentiation and regenerative cycling . Ezhkova's group comprehensively compared the embryonic origin and signalling aspects of Merkel cell specification in hairless paw vs haired dorsal skin and reports on the regional differences . Sundberg et al preformed a large‐scale ageing phenotype screen of nail abnormalities across common inbred mouse strains and reveal previously unappreciated genotype‐dependent nail defect associations.…”