title: A Cascade of Wnt, Eda, and Shh Signaling Is Essential for Touch Dome Merkel Cell Development.
abstract: The Sonic hedgehog (Shh) signaling pathway regulates developmental, homeostatic, and repair processes throughout the body. In the skin, touch domes develop in tandem with primary hair follicles and contain sensory Merkel cells. The developmental signaling requirements for touch dome specification are largely unknown. We found dermal Wnt signaling and subsequent epidermal Eda/Edar signaling promoted Merkel cell morphogenesis by inducing Shh expression in early follicles. Lineage-specific gene deletions revealed intraepithelial Shh signaling was necessary for Merkel cell specification. Additionally, a Shh signaling agonist was sufficient to rescue Merkel cell differentiation in Edar-deficient skin. Moreover, Merkel cells formed in Fgf20 mutant skin where primary hair formation was defective but Shh production was preserved. Although developmentally associated with hair follicles, fate mapping demonstrated Merkel cells primarily originated outside the hair follicle lineage. These findings suggest that touch dome development requires Wnt-dependent mesenchymal signals to establish reciprocal signaling within the developing ectoderm, including Eda signaling to primary hair placodes and ultimately Shh signaling from primary follicles to extrafollicular Merkel cell progenitors. Shh signaling often demonstrates pleiotropic effects within a structure over time. In postnatal skin, Shh is known to regulate the self-renewal, but not the differentiation, of touch dome stem cells. Our findings relate the varied effects of Shh in the touch dome to the ligand source, with locally produced Shh acting as a morphogen essential for lineage specification during development and neural Shh regulating postnatal touch dome stem cell maintenance.
authors.affiliation: Dermatology Branch, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ying
authors.identifier: 0000-0001-7063-8219
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Dermatology Branch, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Thoresen
authors.affiliation: Dermatology Branch, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lingling
authors.initials: L
authors.lastname: Miao
authors.affiliation: Dermatology Branch, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Williams
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Chaochen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Radhika P
authors.initials: RP
authors.lastname: Atit
authors.affiliation: Departments of Dermatology and Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Sunny Y
authors.initials: SY
authors.lastname: Wong
authors.affiliation: Dermatology Branch, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Isaac
authors.identifier: 0000-0002-0090-9914
authors.initials: I
authors.lastname: Brownell
mesh_terms: D000818:Animals; D019070:Cell Lineage; D004260:DNA Repair; D053331:Ectodysplasins / Q000378:metabolism*; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D018859:Hair Follicle / Q000196:embryology / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006706:Homeostasis; D008024:Ligands; D008297:Male; D018862:Merkel Cells / Q000166:cytology*; D051379:Mice; D008856:Microscopy, Fluorescence; D009024:Morphogenesis; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000196:embryology / Q000378:metabolism; D014110:Touch; D051155:Wnt1 Protein / Q000378:metabolism*
chemical_list: D053331:Ectodysplasins; C506019:Eda protein, mouse; C498812:Fgf20 protein, mouse; D053823:Hedgehog Proteins; D008024:Ligands; C465570:Shh protein, mouse; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D005346:Fibroblast Growth Factors