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Spatiotemporal antagonism in mesenchymal-epithelial signaling in sweat versus hair fate decision

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Science  23 Dec 2016:
Vol. 354, Issue 6319, aah6102
DOI: 10.1126/science.aah6102

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How to grow hair or sweat glands

Unlike other mammals that must pant or seek shade or water when overheated, humans are able to self-cool to tolerate extreme heat. Sweat glands, which enable humans to run in marathons, are instrumental for this remarkable feat. Lu et al. investigated skin appendage diversity during development of the furry backs and sweaty paws of mice (see the Perspective by Lai and Chuong). They also examined human skin, which is capable of making both hairs and sweat glands in the same area of the body. Epithelialmesenchymal interactions, with varied signaling pathways that act at specific times in development, are key to producing different skin appendages for adaptation to the environment.

Science, this issue p. 10.1126/science.aah6102; see also p. 1533

Structured Abstract


Across the vertebrate kingdom, epithelial appendages—including mammary, sweat, and salivary glands; hair follicles (HFs); teeth; scales; and feathers—begin to form during embryogenesis when WNT signaling instructs progenitors within the epithelial sheet to organize into morphologically similar placodes. Most animals restrict these epidermal appendages to distinct body regions. This paradigm shifted late in mammalian evolution; the dual presence of HFs and eccrine sweat glands (SwGs) in the skin is a recent acquisition of primates.

Classical tissue recombination experiments from the 1960s revealed that mesenchyme directs the divergent downstream events that determine appendage specification and patterning. Relatively little is known about the specific spatiotemporal cross-talk and molecular mechanisms that underlie epithelial fate specification in response to mesenchymal signals. Elucidating the epithelial-mesenchymal cross-talk involved in regional skin appendage specification is integral to understanding how humans have adjusted these mechanisms to endow them with a greater capacity than that of their hairy cousins to live in diverse environments.


The acquisition of SwGs and their importance in thermoregulation and water balance are underscored by human patients who suffer from the life-threatening condition of lacking SwGs, either from loss in severe burns or from genetic disorders. Conversely, a gain-of-function variant that elevates SwG numbers has been expanding among the Southeast Asian population, where excessive SwGs are desirable. By elucidating the underlying mechanisms that distinguish humans from other mammals in their ability to make both glands and follicles over their body skin, our findings could pave the way for future therapeutic advances in skin regeneration with dual appendages.


Using mouse as a model, we explored the differences between the back skin mesenchyme, which is only competent to specify HFs, and the foot skin mesenchyme, which can only make SwGs. Using genome-wide analyses and functional studies, we discovered that just after the formation of morphologically similar epidermal buds, appendage choice is determined through regional skin differences in mesenchymal expression of bone morphogenetic proteins (BMPs). Probing into mechanisms, we showed that when BMPs are elevated in foot skin mesenchyme, BMP signaling is activated in both dermis and epidermis. This triggers a cascade of downstream signaling events. WNT signaling is elevated in the dermis and reduced in the epidermis. Mesenchymal fibroblast growth factors (FGFs) appear and affect the overlying epithelium. These converging pathways lead to suppression of sonic hedgehog (SHH) in the epithelium.

This BMP:SHH antagonism within the epithelial bud specifies SwG fate and prevents HF fate. Moreover, by manipulating gene expression in vivo at specific developmental stages, we demonstrated that this signaling circuitry acts only within a narrow window of time during mouse embryogenesis. Thus, when SHH is ectopically expressed in foot skin epithelium during the permissive phase, HF-specific gene expression is up-regulated in the epithelial bud, whereas SHH signaling in the mesenchyme stimulates expression of BMP antagonists, further suppressing local BMP signaling and blocking SwG fate. In human skins, this antagonistic interplay of BMP:SHH signaling occurs temporally, in addition to spatially. The first bud waves are specified as HFs, and then a tipping in the balance of BMP:SHH signaling results in the last waves of buds becoming SwGs.


Our findings revealed a differential impact of BMP signaling on appendage fate specification that has ancient roots and occurs repeatedly throughout vertebrate evolution. In the evolutionary developmental biology view of BMP signaling and fate specification of integument, chicken scales and mammalian SwGs require BMP signaling to specify their fate, whereas feathers and HFs must suppress it. Our discovery of BMP-SHH antagonism in bud fate choice uncovered additional evolutionary parallels, this time between two even more distantly related epidermal appendages, the mammalian SwG and the fly wing. Our studies provide new insights into how elevated mesenchymal BMP signaling triggers a self-perpetuating molecular cascade that culminates in silencing of SHH signaling to suppress one appendage fate and specify another. In most mammals, the BMP:SHH antagonism is regulated spatially. Humans, however, have evolved to regulate it temporally, endowing them with greater ability to run marathons and survive in extreme climates.

BMP-SHH antagonism specifies SwG versus HF fate.

To specify SwGs, mesenchymal-derived BMPs and FGFs signal to epithelial buds and suppress epithelially derived SHH production. Conversely, hair follicles are specified when mesenchymal BMP signaling is inhibited, permitting SHH production. This antagonism is spatially restricted in most mammals but temporally regulated in humans, permitting the presence of HFs (pink), SwGs (purple), or both HFs and SwGs (pink with purple droplet) throughout our body skin.


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.

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