839 Spatiotemporal antagonism in mesenchymal-epithelial Signaling in sweat versus hair fate decision

Abstract

The gain of eccrine sweat glands in hairy body skin has empowered humans to run marathons and tolerate temperature extremes. Epithelial-mesenchymal cross-talk is integral to the diverse patterning of skin appendages, but the molecular events underlying their specification remain largely unknown. Using genome-wide analyses and functional studies, we show that sweat glands are specified by mesenchymal-derived bone morphogenetic proteins (BMPs) and fibroblast growth factors that signal to epithelial buds and suppress epithelial-derived sonic hedgehog (SHH) production. Conversely, hair follicles are specified when mesenchymal BMP signaling is blocked, permitting SHH production. Fate determination is confined to a critical developmental window and is regionally specified in mice. In contrast, a shift from hair to gland fates is achieved in humans when a spike in BMP silences SHH during the final embryonic wave(s) of bud morphogenesis.Epithelial appendages-including hair follicles (HFs) and teeth as well as mammary, sweat, and salivary glands-begin to form during embryogenesis when Wnt signaling triggers progenitors within the epithelial sheet to organize spatially into morphologically similar placodes. Whereas most mammals restrict the specification of epidermal appendages regionally, HFs and sweat glands (SwGs) coexist throughout much of the skin of primates. The acquisition of SwGs and their importance in thermoregulation are underscored by humans who suffer from a life-threatening condition when SwGs are eliminated, either from loss in severe burns or from the genetic disorder hypohidrotic ectodermal dysplasia (HED).Patients with HED display mutations in genes encoding proteins such as ectodermal dysplasia antigen (EDA), the EDA receptor (EDAR), and WNT10a, a ligand for Wnt signaling. These findings have illuminated a critical role for these pathways in controlling the development of a number of epidermal appendages, including SwGs and coarse hairs (1, † Corresponding author. fuchslb@rockefeller.edu. * Present address: Calico Life Sciences, South San Francisco, CA 94080, USA.RNAseq data are deposited in the Gene Expression Omnibus under accession number GSE85249 (www.ncbi.nlm.nih.gov/geo).The authors declare no competing financial interests. SUPPLEMENTARY MATERIALS Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript 2). Conversely, an EDAR gain-of-function variant has been expanding among the Southeast Asian population, where excessive SwGs are desirable because of the hot and humid climate of that region (3). In this regard, both Wnt and EDA/EDAR pathways appear to function in promoting placode formation, increasing the density of SwGs and several other appendage types (4).Classical tissue recombination experiments have revealed that mesenchyme plays a critical role in dictating the divergent downstream events that determine appendage selection (5, 6). For example, salivary mesenchyme combined with mammary epithelium generates an epithelial morphology resembling salivary glands (7), and...