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: 33.12). 04/2010; 141(2):331-43. DOI: 10.1016/j.cell.2010.03.013
Source: PubMed

ABSTRACT 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.

  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Cell Reports 07/2015; 7. DOI:10.1016/j.celrep.2015.06.027 · 8.36 Impact Factor
  • Source
    • "The most extensively interconnected gene in Figure 3 is Egfr. This is not entirely surprising, as Egfr is a relatively well-studied gene for its central role in cell proliferation in many organisms, tissues, and in cancer (Yarden, 2001; Cheng et al., 2010). That it features so prominently in this cluster may be somewhat of an artifact due to its overrepresentation in the literature compared to other gene cluster members. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The transition to motherhood involves CNS changes that modify sociability and affective state. However, these changes also put females at risk for postpartum depression and psychosis, which impairs parenting abilities and adversely affects children. Thus, changes in expression and interactions in a core subset of genes may be critical for emergence of a healthy maternal phenotype, but inappropriate changes of the same genes could put women at risk for postpartum disorders. This study evaluated microarray gene expression changes in medial prefrontal cortex (mPFC), a region implicated in both maternal behavior and psychiatric disorders. Postpartum mice were compared to virgin controls housed with females and isolated for identical durations. Using the Modular Single-set Enrichment Test (MSET), we found that the genetic landscape of maternal mPFC bears statistical similarity to gene databases associated with schizophrenia (5 of 5 sets) and bipolar disorder (BPD, 3 of 3 sets). In contrast to previous studies of maternal lateral septum and medial preoptic area, enrichment of autism and depression-linked genes was not significant (2 of 9 sets, 0 of 4 sets). Among genes linked to multiple disorders were fatty acid binding protein 7 (Fabp7), glutamate metabotropic receptor 3 (Grm3), platelet derived growth factor, beta polypeptide (Pdgfrb), and nuclear receptor subfamily 1, group D, member 1 (Nr1d1). RT-qPCR confirmed these gene changes as well as FMS-like tyrosine kinase 1 (Flt1) and proenkephalin (Penk). Systems-level methods revealed involvement of developmental gene networks in establishing the maternal phenotype and indirectly suggested a role for numerous microRNAs and transcription factors in mediating expression changes. Together, this study suggests that a subset of genes involved in shaping the healthy maternal brain may also be dysregulated in mental health disorders and put females at risk for postpartum psychosis with aspects of schizophrenia and BPD.
    Frontiers in Behavioral Neuroscience 04/2014; 8:110. DOI:10.3389/fnbeh.2014.00110 · 4.16 Impact Factor
  • Source
    • "Oocyte Collection Six-to ten-week-old females (CD1, TrpV3 À/À colony; Cheng et al., 2010) were superovulated with intraperitoneal (i.p.) injection of 5 IU pregnant mare's serum gonadotropin (PSMG, Calbiochem, EMD Biosciences), followed 48 hr later by i.p. injection of 5 IU of human chorionic gonadotropin (hCG, Calbiochem, EMD Biosciences). Ovulated eggs (cumulus masses) were obtained by pulling the oviducts open with fine forceps in a HEPESbuffered culture medium (M2 medium, Millipore) 13–16 hr after administration of hCG. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In mammals, calcium influx is required for oocyte maturation and egg activation. The molecular identities of the calcium-permeant channels that underlie the initiation of embryonic development are not established. Here, we describe a transient receptor potential (TRP) ion channel current activated by TRP agonists that is absent in TrpV3(-/-) eggs. TRPV3 current is differentially expressed during oocyte maturation, reaching a peak of maximum density and activity at metaphase of meiosis II (MII), the stage of fertilization. Selective activation of TRPV3 channels provokes egg activation by mediating massive calcium entry. Widely used to activate eggs, strontium application is known to yield normal offspring in combination with somatic cell nuclear transfer. We show that TRPV3 is required for strontium influx, because TrpV3(-/-) eggs failed to conduct Sr(2+) or undergo strontium-induced activation. We propose that TRPV3 is a major mediator of calcium influx in mouse eggs and is a putative target for artificial egg activation.
    Cell Reports 12/2013; 5(5). DOI:10.1016/j.celrep.2013.11.007 · 8.36 Impact Factor
Show more