Research Article| Volume 71, ISSUE 3, P203-209, September 2013

Hairless down-regulates expression of Msx2 and its related target genes in hair follicles

  • Bong-Kyu Kim
    Department of Medical Lifesciences, The Catholic University of Korea, Seoul, Republic of Korea
    Search for articles by this author
  • Sungjoo K. Yoon
    Corresponding author at: Department of Medical Lifesciences, The Catholic University of Korea, Seochogu, Banpodong 505, Seoul 137-701, Republic of Korea. Tel.: +82 0222587474.
    Department of Medical Lifesciences, The Catholic University of Korea, Seoul, Republic of Korea
    Search for articles by this author



      Hairless (HR), a transcriptional cofactor, plays important roles in hair follicle (HF) morphogenesis and cycling. Recently, we reported the new Hr mutant mouse called “Hairpoor” (HrHp) that causes HR overexpression through translational de-repression. The Msh homeobox 2 (Msx2) is a homolog of the Drosophila muscle segment homeobox (msh) gene, which expressed in the hair bulb, including in the germinal matrix, and its expression spreads into the upper region of the HF including the hair cortex.


      Although Msx2 is regarded as an important gene in hair cycle control and hair shaft differentiation, the regulation of Msx2 expression is not well-known.


      Using realtime polymerase chain reaction (PCR) and western blot, we investigated the relationship between HR and Msx2 in the HrHp/HrHp mouse during the HF morphogenesis. Immunohistochemistry was performed to compare the pattern of expression of MSX2 in HrHp/HrHp mouse skin with that in wild-type skin. Msx2 mRNA expression and promoter activity was estimated using a transient expression system to see whether HR down-regulates Msx2 expression in vitro. We also investigated whether downregulation of MSX2 by HR also affects the MSX2 regulatory pathway in the HrHp/HrHp mouse and in an in vitro system.


      We found that the expression of Msx2 was down-regulated by HR, which in turn down-regulated expression of Foxn1 and Lef1, MSX2 target genes, in vivo as well as in vitro.


      Our results show that HR regulates expression of genes in the MSX2 regulatory pathway, which explains abnormal HF formation in HrHp/HrHp skin.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Dermatological Science
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Hardy M.H.
        The secret life of the hair follicle.
        Trends Genet. 1992; 8: 55-61
        • Stenn K.S.
        • Paus R.
        Controls of hair follicle cycling.
        Physiol Rev. 2001; 81: 449-494
        • Krause K.
        • Foitzik K.
        Biology of the hair follicle: the basics.
        Semin Cutan Med Surg. 2006; 25: 2-10
        • Panteleyev A.A.
        • Paus R.
        • Christiano A.M.
        Patterns of hairless (hr) gene expression in mouse hair follicle morphogenesis and cycling.
        Am J Pathol. 2000; 157: 1071-1079
        • Cachon-Gonzalez M.B.
        • Fenner S.
        • Coffin J.M.
        • Moran C.
        • Best S.
        • Stoye J.P.
        Structure and expression of the hairless gene of mice.
        Proc Natl Acad Sci U S A. 1994; 91: 7717-7721
        • Hsieh J.C.
        • Sisk J.M.
        • Jurutka P.W.
        • Haussler C.A.
        • Slater S.A.
        • Haussler M.R.
        • et al.
        Physical and functional interaction between the vitamin D receptor and hairless corepressor, two proteins required for hair cycling.
        J Biol Chem. 2003; 278: 38665-38674
        • Moraitis A.N.
        • Giguere V.
        • Thompson C.C.
        Novel mechanism of nuclear receptor corepressor interaction dictated by activation function 2 helix determinants.
        Mol Cell Biol. 2002; 22: 6831-6841
        • Thompson C.C.
        • Bottcher M.C.
        The product of a thyroid hormone-responsive gene interacts with thyroid hormone receptors.
        Proc Natl Acad Sci U S A. 1997; 94: 8527-8532
        • Zarach J.M.
        • Beaudoin III, G.M.
        • Coulombe P.A.
        • Thompson C.C.
        The co-repressor hairless has a role in epithelial cell differentiation in the skin.
        Development. 2004; 131: 4189-4200
        • Ahmad W.
        • Panteleyev A.A.
        • Sundberg J.P.
        • Christiano A.M.
        Molecular basis for the rhino (hrrh-8J) phenotype: a nonsense mutation in the mouse hairless gene.
        Genomics. 1998; 53: 383-386
        • Mann S.J.
        Hair loss and cyst formation in hairless and rhino mutant mice.
        Anat Rec. 1971; 170: 485-499
        • Zhang J.T.
        • Fang S.G.
        • Wang C.Y.
        A novel nonsense mutation and polymorphisms in the mouse hairless gene.
        J Invest Dermatol. 2005; 124: 1200-1205
        • Baek I.C.
        • Kim J.K.
        • Cho K.H.
        • Cha D.S.
        • Cho J.W.
        • Park J.K.
        • et al.
        A novel mutation in Hr causes abnormal hair follicle morphogenesis in hairpoor mouse, an animal model for Marie Unna Hereditary Hypotrichosis.
        Mamm Genome. 2009; 20: 350-358
        • Kim J.K.
        • Kim E.
        • Baek I.C.
        • Kim B.K.
        • Cho A.R.
        • Kim T.Y.
        • et al.
        Overexpression of Hr links excessive induction of Wnt signaling to Marie Unna hereditary hypotrichosis.
        Hum Mol Genet. 2010; 19: 445-453
        • Wen Y.
        • Liu Y.
        • Xu Y.
        • Zhao Y.
        • Hua R.
        • Wang K.
        • et al.
        Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis.
        Nat Genet. 2009; 41: 228-233
        • Davidson D.
        The function and evolution of Msx genes: pointers and paradoxes.
        Trends Genet. 1995; 11: 405-411
        • Alappat S.
        • Zhang Z.Y.
        • Chen Y.P.
        Msx homeobox gene family and craniofacial development.
        Cell Res. 2003; 13: 429-442
        • Jabs E.W.
        • Muller U.
        • Li X.
        • Ma L.
        • Luo W.
        • Haworth I.S.
        • et al.
        A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis.
        Cell. 1993; 75: 443-450
        • Vi-Fane B.
        • Fernandes I.
        • Davideau J.L.
        Msx1 and its influence on craniofacial growth.
        Orthod Fr. 2007; 78: 39-48
        • Andl T.
        • Ahn K.
        • Kairo A.
        • Chu E.Y.
        • Wine-Lee L.
        • Reddy S.T.
        • et al.
        Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development.
        Development. 2004; 131: 2257-2268
        • Ma L.
        • Liu J.
        • Wu T.
        • Plikus M.
        • Jiang T.X.
        • Bi Q.
        • et al.
        ‘Cyclic alopecia’ in Msx2 mutants: defects in hair cycling and hair shaft differentiation.
        Development. 2003; 130: 379-389
        • Nam Y.
        • Kim J.K.
        • Cha D.S.
        • Cho J.W.
        • Cho K.H.
        • Yoon S.
        • et al.
        A novel missense mutation in the mouse hairless gene causes irreversible hair loss: genetic and molecular analyses of Hr m1Enu.
        Genomics. 2006; 87: 520-526
        • Kim B.K.
        • Baek I.C.
        • Lee H.Y.
        • Kim J.K.
        • Song H.H.
        • Yoon S.K.
        Gene expression profile of the skin in the ‘hairpoor’ (HrHp) mice by microarray analysis.
        BMC genomics. 2010; 11: 640
        • Choi J.H.
        • Kim B.K.
        • Kim J.K.
        • Lee H.Y.
        • Park J.K.
        • Yoon S.K.
        Downregulation of Foxe1 by HR suppresses Msx1 expression in the hair follicles of Hr(Hp) mice.
        BMB Rep. 2011; 44: 478-483
        • Beaudoin III, G.M.
        • Sisk J.M.
        • Coulombe P.A.
        • Thompson C.C.
        Hairless triggers reactivation of hair growth by promoting Wnt signaling.
        Proc Natl Acad Sci U S A. 2005; 102: 14653-14658
        • Kim B.K.
        • Lee H.Y.
        • Choi J.H.
        • Kim J.K.
        • Yoon J.B.
        • Yoon S.K.
        Hairless plays a role in formation of inner root sheath via regulation of Dlx3 gene.
        J Biol Chem. 2012; 287: 16681-16688
        • Nakamura Y.
        • Ichinohe M.
        • Hirata M.
        • Matsuura H.
        • Fujiwara T.
        • Igarashi T.
        • et al.
        Phospholipase C-delta1 is an essential molecule downstream of Foxn1, the gene responsible for the nude mutation, in normal hair development.
        FASEB J. 2008; 22: 841-849
        • Meier N.
        • Dear T.N.
        • Boehm T.
        Whn and mHa3 are components of the genetic hierarchy controlling hair follicle differentiation.
        Mech Dev. 1999; 89: 215-221
        • Cai J.
        • Lee J.
        • Kopan R.
        • Ma L.
        Genetic interplays between Msx2 and Foxn1 are required for Notch1 expression and hair shaft differentiation.
        Dev Biol. 2009; 326: 420-430
        • DasGupta R.
        • Fuchs E.
        Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation.
        Development. 1999; 126: 4557-4568
        • Zhou P.
        • Byrne C.
        • Jacobs J.
        • Fuchs E.
        Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate.
        Genes Dev. 1995; 9: 700-713