TRP Channel Regulates EGFR Signaling in Hair Morphogenesis and Skin Barrier Formation

The Department of Molecular, Cellular, and Developmental Biology, the University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, MI 48109, USA.
Cell (Impact Factor: 32.24). 04/2010; 141(2):331-43. DOI: 10.1016/j.cell.2010.03.013
Source: PubMed


A plethora of growth factors regulate keratinocyte proliferation and differentiation that control hair morphogenesis and skin barrier formation. Wavy hair phenotypes in mice result from naturally occurring loss-of-function mutations in the genes for TGF-alpha and EGFR. Conversely, excessive activities of TGF-alpha/EGFR result in hairless phenotypes and skin cancers. Unexpectedly, we found that mice lacking the Trpv3 gene also exhibit wavy hair coat and curly whiskers. Here we show that keratinocyte TRPV3, a member of the transient receptor potential (TRP) family of Ca(2+)-permeant channels, forms a signaling complex with TGF-alpha/EGFR. Activation of EGFR leads to increased TRPV3 channel activity, which in turn stimulates TGF-alpha release. TRPV3 is also required for the formation of the skin barrier by regulating the activities of transglutaminases, a family of Ca(2+)-dependent crosslinking enzymes essential for keratinocyte cornification. Our results show that a TRP channel plays a role in regulating growth factor signaling by direct complex formation.

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    • "Huang et al., 2011). TRPV3 activation also inhibits hair shaft elongation and induces the premature regression of hair follicles (Borbíró et al., 2011; Cheng et al., 2010), whereas TRPV3 KO mice have curly whiskers and wavy hair (Cheng et al., 2010). These data suggest that the hypomorphic mammoth TRPV3 may have phenocopied TRPV3-null mice and contributed to evolution of cold tolerance, long hair, and large adipose stores in mammoths. "
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    ABSTRACT: Woolly mammoths and living elephants are characterized by major phenotypic differences that have allowed them to live in very different environments. To identify the genetic changes that underlie the suite of woolly mammoth adaptations to extreme cold, we sequenced the nuclear genome from three Asian elephants and two woolly mammoths, and we identified and functionally annotated genetic changes unique to woolly mammoths. We found that genes with mammoth-specific amino acid changes are enriched in functions related to circadian biology, skin and hair development and physiology, lipid metabolism, adipose development and physiology, and temperature sensation. Finally, we resurrected and functionally tested the mammoth and ancestral elephant TRPV3 gene, which encodes a temperature-sensitive transient receptor potential (thermoTRP) channel involved in thermal sensation and hair growth, and we show that a single mammoth-specific amino acid substitution in an otherwise highly conserved region of the TRPV3 channel strongly affects its temperature sensitivity. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Cell Reports
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    • "Briefly, this heat-activated cation channel is expressed in skin, sensory neurons , and epidermal keratinocytes and is stimulated at temperatures >33 °C in mice (Moqrich et al. 2005). Intriguingly, this channel also co-localizes with hair follicles, where it further operates as a regulator of hair morphogenesis (Cheng et al. 2010). Functional expression of the mammoth and inferred ancestral Asian elephant – mammoth TRPV3 channels in HEK293 cells revealed that while the activation temperatures (29 °C) of both proteins were similar, the maximal activity of mammoth TRPV3 was reduced by 20% relative to that of the ancestral elephantid Ca 2+ channel (Lynch et al. 2015). "
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    ABSTRACT: Anatomical changes in extinct mammalian lineages over evolutionary time, such as the loss of fingers and teeth and the rapid increase in body size that accompanied the late Miocene dispersal of the progenitors of Steller’s sea cows (Hydrodamalis gigas (Zimmermann, 1780)) into North Pacific waters and the convergent development of a thick pelage and accompanying reductions in ear and tail surface area of woolly mammoths (Mammuthus primigenius (Blumenbach, 1799)) and woolly rhinoceros (Coelodonta antiquitatis (Blumenbach, 1799)), are prime examples of adaptive evolution underlying the exploitation of new habitats. It is likely, however, that biochemical specializations adopted during these evolutionary transitions were of similar or even greater biological importance. As these “living” processes do not fossilize, direct information regarding the physiological attributes of extinct species has largely remained beyond the range of scientific inquiry. However, the ability to retrieve genomic sequences from ancient DNA samples, combined with ectopic expression systems, now permit the evolutionary origins and structural and functional properties of authentic prehistoric proteins to be examined in great detail. Exponential technical advances in ancient DNA retrieval, enrichment, and sequencing will soon permit targeted generation of complete genomes from hundreds of extinct species across the last one million years that, in combination with emerging in vitro expression, genome engineering, and cell differentiation techniques, promises to herald an exciting new trajectory of evolutionary research at the interface of biochemistry, genomics, palaeontology, and cell biology.
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    • "This might also be the case for AQP5, as AQP5-null mice have no reported skin abnormalities (Song et al., 2002), although the anatomy of the skin has not been directly studied in these mice. However, mice lacking TRPV3 expression in keratinocytes exhibit a significantly thinner stratum corneum, altered keratinocyte differentiation and impaired barrier function (Cheng et al., 2010), whereas AQP3-null mice retain normal barrier function, but display delayed barrier recovery after disruption (Hara et al., 2002). It remains to be seen whether the loss of functional AQP5 and TRPV3 has an effect on epidermal barrier function in human skin and whether any AQP3 variants will be associated with a human skin phenotype in the future. "
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    ABSTRACT: Channels are integral membrane proteins that form a pore, allowing the passive movement of ions or molecules across a membrane (along a gradient), either between compartments within a cell, between intracellular and extracellular environments or between adjacent cells. The ability of cells to communicate with one another and with their environment is a crucial part of the normal physiology of a tissue that allows it to carry out its function. Cell communication is particularly important during keratinocyte differentiation and formation of the skin barrier. Keratinocytes in the skin epidermis undergo a programme of apoptosis-driven terminal differentiation, whereby proliferating keratinocytes in the basal (deepest) layer of the epidermis stop proliferating, exit the basal layer and move up through the spinous and granular layers of the epidermis to form the stratum corneum, the external barrier. Genes encoding different families of channel proteins have been found to harbour mutations linked to a variety of rare inherited monogenic skin diseases. In this Commentary, we discuss how human genetic findings in aquaporin (AQP) and transient receptor potential (TRP) channels reveal different mechanisms by which these channel proteins function to ensure the proper formation and maintenance of the skin barrier.
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