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Cell and Tissue Research

, Volume 364, Issue 1, pp 149–158 | Cite as

Hoxc13 is a crucial regulator of murine hair cycle

  • Weiming Qiu
  • Mingxing Lei
  • Hui Tang
  • Hongtao Yan
  • Xuhong Wen
  • Wei Zhang
  • Ranjing Tan
  • Duan Wang
  • Jinjin WuEmail author
Regular Article

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.

Keywords

Hoxc13 Hair cycle Apoptosis Proliferation Phosphorylated smad2 

Abbreviations

DKK1

Dickkopf 1

IRS

Inner root sheath

ORS

Outer root sheath

PAGE

Polyacrylamide gel electrophoresis

PBS

Phosphate-buffered saline

PVDF

Polyvinylidene fluoride

Notes

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.

Supplementary material

441_2015_2312_MOESM1_ESM.doc (10.7 mb)
ESM 1 (DOC 11005 kb)

References

  1. Alonso L, Fuchs E (2006) The hair cycle. J Cell Sci 119:391–393CrossRefPubMedGoogle Scholar
  2. 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 14:752–760PubMedGoogle Scholar
  3. Godwin AR, Capecchi MR (1998) Hoxc13 mutant mice lack external hair. Genes Dev 12:11–20CrossRefPubMedPubMedCentralGoogle Scholar
  4. Hwang J, Mehrani T, Millar SE, Morasso MI (2008) Dlx3 is a crucial regulator of hair follicle differentiation and cycling. Development 135:3149–3159CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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 277:3718–3726CrossRefPubMedGoogle Scholar
  6. 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 23:486–491CrossRefPubMedGoogle Scholar
  7. 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 3:3260–3269CrossRefPubMedPubMedCentralGoogle Scholar
  8. Kwack MH, Kim MK, Kim JC, Sung YK (2012) Dickkopf 1 promotes regression of hair follicles. J Investig Dermatol 132:1554–1560CrossRefPubMedGoogle Scholar
  9. Li J, Jiang TX, Chuong CM (2013) Many paths to alopecia via compromised regeneration of hair follicle stem cells. J Investig Dermatol 133:1450–1452CrossRefPubMedPubMedCentralGoogle Scholar
  10. 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 91:906–911CrossRefPubMedPubMedCentralGoogle Scholar
  11. Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791CrossRefPubMedGoogle Scholar
  12. 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 117:3–15CrossRefPubMedGoogle Scholar
  13. 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 372:81–87CrossRefPubMedGoogle Scholar
  14. 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 132:1075–1083CrossRefPubMedPubMedCentralGoogle Scholar
  15. 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 144:719–734Google Scholar
  16. 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 279:51524–51533CrossRefPubMedGoogle Scholar
  17. 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 11:1022–1028CrossRefPubMedPubMedCentralGoogle Scholar
  18. Soma T, Tsuji Y, Hibino T (2002) Involvement of transforming growth factor-beta2 in catagen induction during the human hair cycle. J Investig Dermatol 118:993–997CrossRefPubMedGoogle Scholar
  19. Soma T, Dohrmann CE, Hibino T, Raftery LA (2003) Profile of transforming growth factor-beta responses during the murine hair cycle. J Investig Dermatol 121:969–975CrossRefPubMedGoogle Scholar
  20. 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 110:110–115CrossRefPubMedGoogle Scholar
  21. Stenn KS, Paus R (2001) Controls of hair follicle cycling. Physiol Rev 81:449–494PubMedGoogle Scholar
  22. 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 274:318–333CrossRefPubMedGoogle Scholar
  23. 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 128:1547–1558PubMedGoogle Scholar
  24. 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 33:4475–4484CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Weiming Qiu
    • 1
  • Mingxing Lei
    • 2
  • Hui Tang
    • 1
  • Hongtao Yan
    • 1
  • Xuhong Wen
    • 1
  • Wei Zhang
    • 1
  • Ranjing Tan
    • 1
  • Duan Wang
    • 1
  • Jinjin Wu
    • 1
    Email author
  1. 1.Department of Dermatology, Daping HospitalThe Third Military Medical UniversityChongqingChina
  2. 2.“111” Project Laboratory of Biomechanics and Tissue Repair, College of BioengineeringChongqing UniversityChongqingChina

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