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

Abstract

Summary 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-α and EGFR. Conversely, excessive activities of TGF-α/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 Ca2+-permeant channels, forms a signaling complex with TGF-α/EGFR. Activation of EGFR leads to increased TRPV3 channel activity, which in turn stimulates TGF-α release. TRPV3 is also required for the formation of the skin barrier by regulating the activities of transglutaminases, a family of Ca2+-dependent cross-linking enzymes essential for keratinocyte cornification. Our results show that a TRP channel plays a role in regulating growth factor signaling by direct complex formation.

Defective channels lead to an impaired skin barrier

“…Although skin barrier integrity has not been measured in Olmsted syndrome patients, embryonic day 17 TRPV3-null mouse embryos show significant dye permeability compared with control embryos, indicating a defect in barrier integrity in the absence of TRPV3 in the mouse (Cheng et al, 2010). Also in mice, TRPV3 has been shown to regulate epidermal growth factor receptor (EGFR) signalling as well as the activity of transglutaminases, enzymes that crosslink proteins during the formation of the cornified envelope (Cheng et al, 2010). The EGFR signalling pathway is important for the balance between keratinocyte proliferation and differentiation (Schneider et al, 2008) and, in TRPV3-null mouse skin, the level of EGFR activity is reduced (Cheng et al, 2010).…”

“…These gainof-function mutations in TRPV3 result in increased levels of keratinocyte apoptosis, leading to the formation of hyperkeratotic plaques (Lin et al, 2012). Although skin barrier integrity has not been measured in Olmsted syndrome patients, embryonic day 17 TRPV3-null mouse embryos show significant dye permeability compared with control embryos, indicating a defect in barrier integrity in the absence of TRPV3 in the mouse (Cheng et al, 2010). Also in mice, TRPV3 has been shown to regulate epidermal growth factor receptor (EGFR) signalling as well as the activity of transglutaminases, enzymes that crosslink proteins during the formation of the cornified envelope (Cheng et al, 2010).…”

“…Also in mice, TRPV3 has been shown to regulate epidermal growth factor receptor (EGFR) signalling as well as the activity of transglutaminases, enzymes that crosslink proteins during the formation of the cornified envelope (Cheng et al, 2010). The EGFR signalling pathway is important for the balance between keratinocyte proliferation and differentiation (Schneider et al, 2008) and, in TRPV3-null mouse skin, the level of EGFR activity is reduced (Cheng et al, 2010). Furthermore, TRPV3-null mice also exhibit a 'wavy' hair phenotype (Cheng et al, 2010), similar to transforming growth factor-a (TGFa) and EGFRknockout mice (Luetteke et al, 1993;Mann et al, 1993), supporting the link with EGFR signalling.…”

“…The EGFR signalling pathway is important for the balance between keratinocyte proliferation and differentiation (Schneider et al, 2008) and, in TRPV3-null mouse skin, the level of EGFR activity is reduced (Cheng et al, 2010). Furthermore, TRPV3-null mice also exhibit a 'wavy' hair phenotype (Cheng et al, 2010), similar to transforming growth factor-a (TGFa) and EGFRknockout mice (Luetteke et al, 1993;Mann et al, 1993), supporting the link with EGFR signalling. By contrast, Olmsted syndrome patients with activating TRPV3 mutations exhibit diffuse alopecia, and mice carrying gain-of-function TRPV3 mutations are hairless (Asakawa et al, 2006;Xiao et al, 2008).…”

“…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 . 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.…”