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Hoxc13 is a crucial regulator of murine hair cycle

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Abstract

Hair follicles undergo cyclical growth and regression during postnatal life. Hair regression is an apoptosis-driven process strictly controlled by micro- and macro-environmental signals. However, how these signals are controlled remains largely unknown. Hoxc13, a member of the Hox gene family, is reported to play an important role in hair follicle differentiation. In the present study, we observed that Hoxc13 was highly expressed in the outer root sheath, matrix, medulla and inner root sheath of hair follicles in a hair cycle-dependent manner. We therefore investigated the role of Hoxc13 in hair follicle cycling. Injection of ShRNA (ShHoxc13) to suppress Hoxc13 in early anagen promoted premature catagen entry, shown by significantly decreased hair length and hair bulb size, increased percentage of catagen hair follicles, hair cycle score and TUNEL+ cells and inhibited proliferation. In contrast, local injection of recombinant Hoxc13 polypeptide (rhHoxc13) during the late anagen phase prolonged the anagen phase. Additionally, rhHoxc13 injections during the telogen phase significantly promoted hair growth and induced the anagen progression. At the molecular level, the expression of phosphorylated smad2 (p-smad2), a key factor of active TGF-β1 signaling, was up-regulated in the ShHoxc13-treated hair follicles and down-regulated in rhHoxc13-treated hair follicles, suggesting that Hoxc13 might block anagen–catagen transition by inhibiting the TGF-β1 signaling. Taken together, our data strongly suggest that Hoxc13 is a novel and crucial regulator of the hair cycle. This might also provide an understanding of the mechanism of the ‘hair cycle clock’ and the development of alopecia treatments.

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Abbreviations

DKK1:

Dickkopf 1

IRS:

Inner root sheath

ORS:

Outer root sheath

PAGE:

Polyacrylamide gel electrophoresis

PBS:

Phosphate-buffered saline

PVDF:

Polyvinylidene fluoride

References

  • Alonso L, Fuchs E (2006) The hair cycle. J Cell Sci 119:391–393

    Article  CAS  PubMed  Google Scholar 

  • Foitzik K, Lindner G, Mueller-Roever S, Maurer M, Botchkareva N, Botchkarev V, Handjiski B, Metz M, Hibino T, Soma T, Dotto GP, Paus R (2000) Control of murine hair follicle regression (catagen) by TGF-beta1 in vivo. FASEB J 14:752–760

    CAS  PubMed  Google Scholar 

  • Godwin AR, Capecchi MR (1998) Hoxc13 mutant mice lack external hair. Genes Dev 12:11–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hwang J, Mehrani T, Millar SE, Morasso MI (2008) Dlx3 is a crucial regulator of hair follicle differentiation and cycling. Development 135:3149–3159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jave-Suarez LF, Winter H, Langbein L, Rogers MA, Schweizer J (2002) HOXC13 is involved in the regulation of human hair keratin gene expression. J Biol Chem 277:3718–3726

    Article  CAS  PubMed  Google Scholar 

  • Jing J, Wu XJ, Li YL, Cai SQ, Zheng M, Lu ZF (2014) Expression of decorin throughout the murine hair follicle cycle: hair cycle dependence and anagen phase prolongation. Exp Dermatol 23:486–491

    Article  CAS  PubMed  Google Scholar 

  • Kasiri S, Ansari KI, Hussain I, Bhan A, Mandal SS (2013) Antisense oligonucleotide mediated knockdown of HOXC13 affects cell growth and induces apoptosis in tumor cells and over expression of HOXC13 induces 3D-colony formation. RSC Adv 3:3260–3269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwack MH, Kim MK, Kim JC, Sung YK (2012) Dickkopf 1 promotes regression of hair follicles. J Investig Dermatol 132:1554–1560

    Article  CAS  PubMed  Google Scholar 

  • Li J, Jiang TX, Chuong CM (2013) Many paths to alopecia via compromised regeneration of hair follicle stem cells. J Investig Dermatol 133:1450–1452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin Z, Chen Q, Shi L, Lee M, Giehl KA, Tang Z, Wang H, Zhang J, Yin J, Wu L, Xiao R, Liu X, Dai L, Zhu X, Li R, Betz RC, Zhang X, Yang Y (2012) Loss-of-function mutations in HOXC13 cause pure hair and nail ectodermal dysplasia. Am J Hum Genet 91:906–911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791

    Article  CAS  PubMed  Google Scholar 

  • Muller-Rover S, Handjiski B, van der Veen C, Eichmuller S, Foitzik K, McKay IA, Stenn KS, Paus R (2001) A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Investig Dermatol 117:3–15

    Article  CAS  PubMed  Google Scholar 

  • Niimori D, Kawano R, Felemban A, Niimori-Kita K, Tanaka H, Ihn H, Ohta K (2012) Tsukushi controls the hair cycle by regulating TGF-beta1 signaling. Dev Biol 372:81–87

    Article  CAS  PubMed  Google Scholar 

  • Oda Y, Hu L, Bul V, Elalieh H, Reddy JK, Bikle DD (2012) Coactivator MED1 ablation in keratinocytes results in hair-cycling defects and epidermal alterations. J Investig Dermatol 132:1075–1083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paus R, Handjiski B, Eichmüller S, Czarnetzki BM (1994) Chemotherapy-induced alopecia in mice. Induction by cyclophosphamide, inhibition by cyclosporine A, and modulation by DEX. Am J Pathol 1994 144:719–734

  • Pruett ND, Tkatchenko TV, Jave-Suarez L, Jacobs DF, Potter CS, Tkatchenko AV, Schweizer J, Awgulewitsch A (2004) Krtap16, characterization of a new hair keratin-associated protein (KAP) gene complex on mouse chromosome 16 and evidence for regulation by Hoxc13. J Biol Chem 279:51524–51533

    Article  CAS  PubMed  Google Scholar 

  • Qiu W, Lei M, Li J, Wang N, Lian X (2014) Activated hair follicle stem cells and Wnt/beta-catenin signaling involve in pathnogenesis of sebaceous neoplasms. Int J Med Sci 11:1022–1028

    Article  PubMed  PubMed Central  Google Scholar 

  • Soma T, Tsuji Y, Hibino T (2002) Involvement of transforming growth factor-beta2 in catagen induction during the human hair cycle. J Investig Dermatol 118:993–997

    Article  CAS  PubMed  Google Scholar 

  • Soma T, Dohrmann CE, Hibino T, Raftery LA (2003) Profile of transforming growth factor-beta responses during the murine hair cycle. J Investig Dermatol 121:969–975

    Article  CAS  PubMed  Google Scholar 

  • Stelnicki EJ, Komuves LG, Kwong AO, Holmes D, Klein P, Rozenfeld S, Lawrence HJ, Adzick NS, Harrison M, Largman C (1998) HOX homeobox genes exhibit spatial and temporal changes in expression during human skin development. J Investig Dermatol 110:110–115

    Article  CAS  PubMed  Google Scholar 

  • Stenn KS, Paus R (2001) Controls of hair follicle cycling. Physiol Rev 81:449–494

    CAS  PubMed  Google Scholar 

  • Thummel R, Li L, Tanase C, Sarras MP Jr, Godwin AR (2004) Differences in expression pattern and function between zebrafish hoxc13 orthologs: recruitment of Hoxc13b into an early embryonic role. Dev Biol 274:318–333

    Article  CAS  PubMed  Google Scholar 

  • Tkatchenko AV, Visconti RP, Shang L, Papenbrock T, Pruett ND, Ito T, Ogawa M, Awgulewitsch A (2001) Overexpression of Hoxc13 in differentiating keratinocytes results in downregulation of a novel hair keratin gene cluster and alopecia. Development 128:1547–1558

    CAS  PubMed  Google Scholar 

  • Williams TM, Williams ME, Heaton JH, Gelehrter TD, Innis JW (2005) Group 13 HOX proteins interact with the MH2 domain of R-Smads and modulate Smad transcriptional activation functions independent of HOX DNA-binding capability. Nucleic Acids Res 33:4475–4484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Nature Science Foundation of China (Grant number: 31170924) and Fundamental Research Funds for the Central Universities (106112015CDJRC231206) to Mingxing Lei. We thank Dr. Randall B. Widelitz (University of Southern California) for carefully revising the manuscript.

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Correspondence to Jinjin Wu.

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Weiming Qiu and Mingxing Lei contributed equally to this work.

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Qiu, W., Lei, M., Tang, H. et al. Hoxc13 is a crucial regulator of murine hair cycle. Cell Tissue Res 364, 149–158 (2016). https://doi.org/10.1007/s00441-015-2312-7

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