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Overexpression of constitutively active BMP-receptor-IB in mouse skin causes an ichthyosis-vulgaris-like disease

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Abstract

The skin is the outer layer of protection against the environment. The development and formation of the skin is regulated by several genetic cascades including the bone morphogenetic protein (BMP) signaling pathway, which has been suggested to play an important role during embryonic organ development. Several skin defects and diseases are caused by genetic mutations or disorders. Ichthyosis is a common genetic skin disorder characterized by dry scaly skin. Loss-of-function mutations in the filaggrin (FLG) gene have been identified as the cause of the ichthyosis vulgaris (IV) phenotype; however, the direct regulation of filaggrin expression in vivo is unknown. We present evidence that BMP signaling regulates filaggrin expression in the epidermis. Mice expressing a constitutively active form of BMP-receptor-IB in the developing epidermis exhibit a phenotype resembling IV in humans, including dry flaky skin, compact hyperkeratosis, and an attenuated granular layer associated with a significantly downregulated expression of filaggrin. Regulation of filaggrin expression by BMP signaling has been further confirmed by the application of exogenous BMP2 in skin explants and by a transgenic model overexpressing Noggin in the epidermis. Our results demonstrate that aberrant BMP signaling in the epidermis causes overproliferation and hyperkeratinization, leading to an IV-like skin disease.

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References

  • Andreoli JM, Jang SI, Chung E, Coticchia CM, Steinert PM, Markova NG (1997) The expression of a novel, epithelium-specific ETS transcription factor is restricted to the most differentiated layers in the epidermis. Nucleic Acids Res 25:4287–4295

    Article  CAS  PubMed  Google Scholar 

  • Bitgood MJ, McMahon AP (1995) Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev Biol 172:126–138

    Article  CAS  PubMed  Google Scholar 

  • Blessing M, Schirmacher P, Kaiser S (1996) Overexpression of bone morphogenetic protein-6 (BMP-6) in the epidermis of transgenic mice: inhibition or stimulation of proliferation depending on the pattern of transgene expression and formation of psoriatic lesions. J Cell Biol 135:227–239

    Article  CAS  PubMed  Google Scholar 

  • Botchkarev VA, Sharov AA (2004) BMP signaling in the control of skin development and hair follicle growth. Differentiation 72:512–526

    Article  CAS  PubMed  Google Scholar 

  • Botchkarev VA, Botchkareva NV, Roth W, Nakamura M, Chen LH, Herzog W, Lindner G, McMahon JA, Peters C, Lauster R, MaMahon AP, Paus R (1999) Noggin is a mesenchymally derived stimulator of hair-follicle induction. Nat Cell Biol 1:158–164

    Article  CAS  PubMed  Google Scholar 

  • Candi E, Schmidt R, Melino G (2005) The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 6:328–340

    Article  CAS  PubMed  Google Scholar 

  • Denecker G, Hoste E, Gilbert B, Hochepied T, Ovaere P, Lippens S, Van den Broecke C, Van Damme P, D’Herde K, Hachem JP, Borgonie G, Presland RB, Schoonjans L, Libert C, Vandekerckhove J, Gevaert K, Vandenabeele P, Declercq W (2007) Caspase-14 protects against epidermal UVB photodamage and water loss. Nat Cell Biol 9:666–674

    Article  CAS  PubMed  Google Scholar 

  • Dijke P ten, Yamashita H, Sampath TK, Reddi AH, Estevez M, Riddle DI, Ichijo H, Heldin C-H, Miyazono K (1994) Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 269:16985–16988

    PubMed  Google Scholar 

  • Fuchs E, Green H (1980) Changes in keratin gene expression during terminal differentiation of the keratinocyte. Cell 19:1033–1042

    Article  CAS  PubMed  Google Scholar 

  • Hardman MJ, Sisi P, Banbury DN, Byrne C (1998) Patterned acquisition of skin barrier function during development. Development 125:1541–1552

    CAS  PubMed  Google Scholar 

  • Hogan BL (1996) Bone morphogenetic proteins in development. Curr Opin Genet Dev 6:432–438

    Article  CAS  PubMed  Google Scholar 

  • Hoodless PA, Haerry T, Abdollah S, Stapleton M, O’Connor MB, Attisano L, Wrana JL (1996) MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell 85:489–500

    Article  CAS  PubMed  Google Scholar 

  • Jang SI, Steinert PM, Markova NG (1996) Activator protein 1 activity is involved in the regulation of the cell type-specific expression from the proximal promoter of the human profilaggrin gene. J Biol Chem 271:24105–24114

    Article  CAS  PubMed  Google Scholar 

  • Jang SI, Karaman-Jurukovska N, Morasso MI, Steinert PM, Markova NG (2000) Complex interactions between epidermal POU domain and activator protein 1 transcription factors regulate the expression of the profilaggrin gene in normal human epidermal keratinocytes. J Biol Chem 275:15295–15304

    Article  CAS  PubMed  Google Scholar 

  • Kawabata M, Imamura T, Miyazono K (1998) Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev 9:49–61

    Article  CAS  PubMed  Google Scholar 

  • Kelsell DP, Norgett EE, Unsworth H, Teh M-T, Cullup T, Mein CA, Dopping-Hepenstal PJ, Dale BA, Tadini G, Fleckman P, Stephens KG, Sybert VP, Mallory SB, North BV, Witt DR, Sprecher E, Taylor AE, Ilchyshyn A, Kennedy CT, Goodyear H, Moss C, Paige D, Harper JI, Young BD, Leigh IM, Eady RA, O’Toole EA (2005) Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am J Hum Genet 76:794–803

    Article  CAS  PubMed  Google Scholar 

  • Kobielak K, Stokes N, de la Cruz J, Polak L, Fuchs E (2007) Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc Natl Acad Sci USA 104:10063–10068

    Article  CAS  PubMed  Google Scholar 

  • Kretzschmar M, Liu F, Hata A, Doody J, Massague J (1997) The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase. Genes Dev 11:984–995

    Article  CAS  PubMed  Google Scholar 

  • Lefevre C, Audebert S, Jobard F, Bouadjar B, Lakhdar H, Boughdene-Stambouli O, Blanchet-Bardon C, Heilig R, Foglio M, Weissenbach J, Lathrop M, Prud’homme JF, Fischer J (2003) Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum Mol Genet 12:2369–2378

    Article  CAS  PubMed  Google Scholar 

  • Lersch R, Fuchs E (1988) Sequence and expression of a type II keratin, K5, in human epidermal cells. Mol Cell Biol 8:486–493

    CAS  PubMed  Google Scholar 

  • Liu P, Yang Q, Wang X, Feng A, Yang T, Yang R, Wang P, Yuang M, Liu M, Liu JY, Wang QK (2007) Identification of a genetic locus for ichthyosis vulgaris on chromosome 10q22.3-q24.2. J Invest Dermatol 128:1418–1422

    Article  PubMed  Google Scholar 

  • Lyons KM, Pelton RW, Hogan BL (1989) Patterns of expression of murine Vgr-1 and BMP-2a RNA suggest that transforming growth factor-beta-like genes coordinately regulate aspects of embryonic development. Genes Dev 3:1657–1668

    Article  CAS  PubMed  Google Scholar 

  • Lyons KM, Pelton RW, Hogan BL (1990) Organogenesis and pattern formation in the mouse: RNA distribution patterns suggest a role for bone morphogenetic protein-2A (BMP-2A). Development 109:833–844

    CAS  PubMed  Google Scholar 

  • McGowan K, Coulombe PA (1998) The wound repair-associated keratins 6, 16, and 17. Insights into the role of intermediate filaments in specifying keratinocyte cytoarchitecture. Subcell Biochem 31:173–204

    CAS  PubMed  Google Scholar 

  • McGrath JA, Uitto J (2008) The filaggrin story: novel insights into skin-barrier function and disease. Trends Mol Med 14:20–27

    Article  CAS  PubMed  Google Scholar 

  • Nelson WG, Sun TT (1983) The 50- and 58-kDalton keratin classes as molecular markers for stratified squamous epithelia: cell culture studies. J Cell Biol 47:244–251

    Article  Google Scholar 

  • Nohe A, Keating E, Knaus P, Petersen NO (2004) Signal transduction of bone morphogenetic protein receptors. Cell Signal 16:291–299

    Article  CAS  PubMed  Google Scholar 

  • Segre JA (2006) Epidermal barrier formation and recovery in skin disorders. J Clin Invest 116:1150–1158

    Article  CAS  PubMed  Google Scholar 

  • Sieber C, Kopf J, Hiepen C, Knaus P (2009) Recent advances in BMP receptor signaling. Cytokine Growth Factor Rev 20:343–355

    Article  CAS  PubMed  Google Scholar 

  • Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y (2006) Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 38:337–342

    Article  CAS  PubMed  Google Scholar 

  • Smyth I, Hacking DF, Hilton AA, Mukhamedova N, Meikle PJ, Ellis S, Satterley A, Collinge JE, Graaf CA de, Bahlo M, Sviridov D, Kile BT, Hilton DJ (2008) A mouse model of harlequin ichthyosis delineates a key role for Abca12 in lipid homeostasis. PLoS Genet 4:e1000192

    Article  PubMed  Google Scholar 

  • Takahashi H, Ikeda T (1996) Transcripts for two members of the transforming growth factor-beta superfamily BMP-3 and BMP-7 are expressed in developing rat embryos. Dev Dyn 207:439–449

    Article  CAS  PubMed  Google Scholar 

  • Thomas AC, Sinclair C, Mahmud N, Cullup T, Mellerio JE, Harper J, Dale BA, Turc-Carel C, Hohl D, McGrath JA, Vahlquist A, Hellstrom-Pigg M, Ganemo A, Metcalfe K, Mein CA, O’Toole EA, Kelsell DP (2008) Novel and recurring ABCA12 mutations associated with harlequin ichthyosis: implications for prenatal diagnosis. Br J Dermatol 158:611–613

    Article  CAS  PubMed  Google Scholar 

  • Wall NA, Blessing M, Wright CV, Hogan BL (1993) Biosynthesis and in vivo localization of the decapentaplegic-Vg-related protein, DVR-6 (bone morphogenetic protein-6). J Cell Biol 120:493–502

    Article  CAS  PubMed  Google Scholar 

  • Wang SS, Yu XY, Zhang T, Zhang XY, Zhang ZY, Chen YP (2004) Chick Pc12 regulates the left-right asymmetry by repressing Shh expression in Hensen’s node. Development 131:4381–4391

    Article  CAS  PubMed  Google Scholar 

  • Wells RS, Kerr CB (1966) Clinical features of autosomal dominant and sex-linked ichthyosis in an English population. BMJ 1:947–950

    Article  CAS  PubMed  Google Scholar 

  • Wieser R, Wrana JL, Massague J (1995) GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J 14:2199–2208

    CAS  PubMed  Google Scholar 

  • Wozney JM, Rosen V, Celeste AJ, Mitsok LM, Whitters MJ, Kris RW, Hewick RM, Wang EA (1988) Novel regulators of bone formation: molecular clones and activities. Science 242:1528–1534

    Article  CAS  PubMed  Google Scholar 

  • Xiong W, He F, Morikawa Y, Yu X, Zhang Z, Lan Y, Jiang R, Cserjesi P, Chen YP (2009) Hand2 is required in the epithelium for palatogenesis in mice. Dev Biol 330:131–141

    Article  CAS  PubMed  Google Scholar 

  • Zhang YD, Zhao X, Hu YP, St Amand T, Zhang MF, Ramamurthy R (1999) Msx1 is required for the induction of Patched by Sonic hedgehog in the mammalian tooth germ. Dev Dyn 215:45–53

    Article  CAS  PubMed  Google Scholar 

  • Zhang ZY, Yu XY, Zhang YD, Geronimo B, Lovlie A, Fromm SH, Chen YP (2000) Targeted misexpression of constitutively active BMP receptor-IB causes bifurcation, duplication, and posterior transformation of digit in mouse limb. Dev Biol 220:154–167

    Article  CAS  PubMed  Google Scholar 

  • Zou H, Wieser R, Massague J, Niswander L (1997) Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage. Genes Dev 11:2191–2203

    Article  CAS  PubMed  Google Scholar 

  • Zuo Y, Zhuang DZ, Han R, Isaac G, Tobin JJ, McKee M, Welti R, Brissette JL, Fitzgerald ML, Freeman MW (2008) ABCA12 maintains the epidermal lipid permeability barrier by facilitating formation of ceramide linoleic esters. J Biol Chem 283:36624–36635

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. Ramón A. Espinoza-Lewis

    Present address: Children’s Hospital Boston-Harvard Medical School, Boston, MA 02115, USA

  2. Fenglei He

    Present address: Mount Sinai Medical School, New York, NY 10029, USA

Authors and Affiliations

  1. Section of Oral Biology, The Ohio State University College of Dentistry, Columbus, OH 43210, USA

    Xueyan Yu, Ramón A. Espinoza-Lewis, Cheng Sun, Lisong Lin, Fenglei He, Wei Xiong & YiPing Chen

  2. Center for Cell & Developmental Biology, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA

    Jing Yang

  3. Department of Pathology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA

    Alun Wang

  4. Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA

    Ramón A. Espinoza-Lewis, Cheng Sun, Fenglei He, Wei Xiong & YiPing Chen

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  1. Xueyan Yu
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Correspondence to YiPing Chen.

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Xueyan Yu and Ramón A. Espinoza-Lewis contributed equally to this work.

This work was supported by grants from the NIH to Y.-P.C.

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Yu, X., Espinoza-Lewis, R.A., Sun, C. et al. Overexpression of constitutively active BMP-receptor-IB in mouse skin causes an ichthyosis-vulgaris-like disease. Cell Tissue Res 342, 401–410 (2010). https://doi.org/10.1007/s00441-010-1077-2

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