Abstract
iRhom2 is necessary for maturation of TNFα-converting enzyme, which is required for the release of tumor necrosis factor. In the previous study, we found that the iRhom2 Uncv mutation in N-terminal cytoplasmic domain-encoding region (iRhom2Uncv) leads to aberrant hair shaft and inner root sheath differentiation, thus results in a hairless phenotype in homozygous iRhom2 Uncv/Uncv BALB/c mice. In this study, we found iRhom2 mutation decreased hair matrix proliferation, however, iRhom2 Uncv/Uncv mice displayed hyperproliferation and hyperkeratosis in the interfollicular epidermis along with hypertrophy in the sebaceous glands. The number of bulge SCs was not altered and the hair follicle cycle is normal in iRhom2 Uncv/Uncv mice. The decreased proliferation in hair matrix but increased proliferation in epidermis and sebaceous glands in iRhom2 Uncv/Uncv mice may implying that iRhom2 Uncv mutation blocks bugle stem cells assuming the fate of hair follicle. This study identifies iRhom2 as a novel regulator for determination of keratinocyte lineages.
Similar content being viewed by others
Abbreviations
- IFE:
-
Interfollicular epidermis
- iRhoms:
-
Inactive rhomboids
- K:
-
Keratin
- P:
-
Postnatal day
- PCR:
-
Polymerase chain reaction
- SG:
-
Sebaceous gland
- Shh:
-
Sonic hedgehog
- SCs:
-
Stem cells
- TACE:
-
TNF-α-converting enzyme
- TNFα:
-
Tumor necrosis factor α
References
Adrain C, Zettl M, Christova Y, Taylor N, Freeman M (2012) Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. Science 335:225–228. doi:10.1126/science.1214400
Blanpain C, Fuchs E (2006) Epidermal stem cells of the skin. Annu Rev Cell Dev Biol 22:339–373. doi:10.1146/annurev.cellbio.22.010305.104357
Blaydon DC, Etheridge SL, Risk JM, Hennies HC, Gay LJ, Carroll R, Plagnol V, McRonald FE, Stevens HP, Spurr NK, Bishop DT, Ellis A, Jankowski J, Field JK, Leigh IM, South AP, Kelsell DP (2012) RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am J Hum Genet 90:340–346. doi:10.1016/j.ajhg.2011.12.008
Braun KM, Niemann C, Jensen UB, Sundberg JP, Silva-Vargas V, Watt FM (2003) Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 130:5241–5255. doi:10.1242/dev.00703
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. doi:10.1038/nrm1619
Chiang C, Swan RZ, Grachtchouk M, Bolinger M, Litingtung Y, Robertson EK, Cooper MK, Gaffield W, Westphal H, Beachy PA, Dlugosz AA (1999) Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev Biol 205:1–9. doi:10.1006/dbio.1998.9103
Cotsarelis G, Sun TT, Lavker RM (1990) Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61:1329–1337
Demehri S, Kopan R (2009) Notch signaling in bulge stem cells is not required for selection of hair follicle fate. Development 136:891–896. doi:10.1242/dev.030700
Dereure O (2012) RHBDF2 mutations in familial palmoplantar keratoderma associated with tylosis oesophageal cancer. Ann Dermatol Venereol 139:605–606. doi:10.1016/j.annder.2012.04.001
Fuchs E (2007) Scratching the surface of skin development. Nature 445:834–842. doi:10.1038/nature05659
Hosur V, Johnson KR, Burzenski LM, Stearns TM, Maser RS, Shultz LD (2014) Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin. Proc Natl Acad Sci USA 111:E2200–E2209. doi:10.1073/pnas.1323908111
Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W (2001) β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105:533–545
Issuree PD, Maretzky T, McIlwain DR, Monette S, Qing X, Lang PA, Swendeman SL, Park-Min KH, Binder N, Kalliolias GD, Yarilina A, Horiuchi K, Ivashkiv LB, Mak TW, Salmon JE, Blobel CP (2013) iRHOM2 is a critical pathogenic mediator of inflammatory arthritis. J Clin Invest 123:928–932. doi:10.1172/JCI66168
Jamora C, DasGupta R, Kocieniewski P, Fuchs E (2003) Links between signal transduction, transcription and adhesion in epithelial bud development. Nature 422:317–322. doi:10.1038/nature01458
Johnson KR, Lane PW, Cook SA, Harris BS, Ward-Bailey PF, Bronson RT, Lyons BL, Shultz LD, Davisson MT (2003) Curly bare (cub), a new mouse mutation on chromosome 11 causing skin and hair abnormalities, and a modifier gene (mcub) on chromosome 5. Genomics 81:6–14
Kaufman CK, Zhou P, Pasolli HA, Rendl M, Bolotin D, Lim KC, Dai X, Alegre ML, Fuchs E (2003) GATA-3: an unexpected regulator of cell lineage determination in skin. Genes Dev 17:2108–2122. doi:10.1101/gad.1115203
Koster MI, Roop DR (2007) Mechanisms regulating epithelial stratification. Annu Rev Cell Dev Biol 23:93–113. doi:10.1146/annurev.cellbio.23.090506.123357
Leilei Y, Bing L, Yang L, Shaoxia W, Yuan X, Dongping W, Huahu Y, Shichen S, Guangzhou Z, Ruiyun P, Lin Z, Wenlong L (2014) iRhom2 mutation leads to aberrant hair follicle differentiation in mice. PLoS One 9:e115114. doi:10.1371/journal.pone.0115114
Lemberg MK, Freeman M (2007) Functional and evolutionary implications of enhanced genomic analysis of rhomboid intramembrane proteases. Genome Res 17:1634–1646. doi:10.1101/gr.6425307
Li SR, Wang DP, Yu XL, Ge BS, Wang CE, Lu YF, Li JQ, Wu N, Li RF, Zhu SE, Zhang ZC, Chen YF (1999) Uncv (uncovered): a new mutation causing hairloss on mouse chromosome 11. Genet Res 73:233–238
Liu B, Xu Y, Li WL, Zeng L (2015) Proteomic analysis of differentially expressed skin proteins in iRhom2(Uncv) mice. BMB Rep 48:19–24
Matsuo K, Mori O, Hashimoto T (1998) Apoptosis in murine hair follicles during catagen regression. Arch Dermatol Res 290:133–136
McIlwain DR, Lang PA, Maretzky T, Hamada K, Ohishi K, Maney SK, Berger T, Murthy A, Duncan G, Xu HC, Lang KS, Haussinger D, Wakeham A, Itie-Youten A, Khokha R, Ohashi PS, Blobel CP, Mak TW (2012) iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS. Science 335:229–232. doi:10.1126/science.1214448
Nowak JA, Polak L, Pasolli HA, Fuchs E (2008) Hair follicle stem cells are specified and function in early skin morphogenesis. Cell Stem Cell 3:33–43. doi:10.1016/j.stem.2008.05.009
Oro AE, Higgins K (2003) Hair cycle regulation of Hedgehog signal reception. Dev Biol 255:238–248
Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y (2001) Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell 104:233–245
Saarinen S, Vahteristo P, Lehtonen R, Aittomaki K, Launonen V, Kiviluoto T, Aaltonen LA (2012) Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer. Fam Cancer 11:525–528. doi:10.1007/s10689-012-9532-8
Shi YZ, Wang DP, Hu LD, Zhao GP, Wang YZ, Kong XY, Li SR (2003) A high-resolution genetic and physical map of a mouse coat abnormality locus (Uncv). Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 35:397–402
Siggs OM, Grieve A, Xu H, Bambrough P, Christova Y, Freeman M (2014) Genetic interaction implicates iRhom2 in the regulation of EGF receptor signalling in mice. Biol Open 3:1151–1157. doi:10.1242/bio.201410116
Siggs OM, Xiao N, Wang Y, Shi H, Tomisato W, Li X, Xia Y, Beutler B (2012) iRhom2 is required for the secretion of mouse TNFalpha. Blood 119:5769–5771. doi:10.1182/blood-2012-03-417949
Taylor G, Lehrer MS, Jensen PJ, Sun TT, Lavker RM (2000) Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102:451–461
Vidal VP, Chaboissier MC, Lutzkendorf S, Cotsarelis G, Mill P, Hui CC, Ortonne N, Ortonne JP, Schedl A (2005) Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr Biol 15:1340–1351. doi:10.1016/j.cub.2005.06.064
Yang L, Wang L, Yang X (2009) Disruption of Smad4 in mouse epidermis leads to depletion of follicle stem cells. Mol Biol Cell 20:882–890. doi:10.1091/mbc.E08-07-0731
Zettl M, Adrain C, Strisovsky K, Lastun V, Freeman M (2011) Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling. Cell 145:79–91. doi:10.1016/j.cell.2011.02.047
Zhang J, He XC, Tong WG, Johnson T, Wiedemann LM, Mishina Y, Feng JQ, Li L (2006) Bone morphogenetic protein signaling inhibits hair follicle anagen induction by restricting epithelial stem/progenitor cell activation and expansion. Stem Cells 24:2826–2839. doi:10.1634/stemcells.2005-0544
Zou H, Thomas SM, Yan ZW, Grandis JR, Vogt A, Li LY (2009) Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in head and neck squamous cancer cells. FASEB J 23:425–432. doi:10.1096/fj.08-112771
Acknowledgments
This work was supported by National Natural Science Foundation of China (31030058, 81272104, 81571905, 81571423). We would like to thank staff of Institute of JingFeng Medical Laboratory Animal for animal husbandry.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
All authors declare no conflict of interest.
Additional information
L. Yang, W. Li equally contributed to this work.
Rights and permissions
About this article
Cite this article
Yang, L., Li, W., Liu, B. et al. iRhom2 Uncv mutation blocks bulge stem cells assuming the fate of hair follicle. Arch Dermatol Res 308, 503–510 (2016). https://doi.org/10.1007/s00403-016-1663-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00403-016-1663-6