{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:46:22Z","timestamp":1791333982842,"version":"4.3.1"},"reference-count":41,"publisher":"The Company of Biologists","issue":"20","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2004,10,15]]},"abstract":"<jats:p>Despite the well-characterised role of sonic hedgehog (Shh) in promoting interfollicular basal cell proliferation and hair follicle downgrowth, the role of hedgehog signalling during epidermal stem cell fate remains largely uncharacterised. In order to determine whether the three vertebrate hedgehog molecules play a role in regulating epidermal renewal we overexpressed sonic(Shh), desert (Dhh) and Indian (Ihh) hedgehog in the basal cells of mouse skin under the control of the human keratin 14 promoter. We observed no overt epidermal morphogenesis phenotype in response to Ihh overexpression, however Dhh overexpression resulted in a range of embryonic and adult skin manifestations indistinguishable from Shh overexpression. Two distinct novel phenotypes were observed amongst Shh and Dhh transgenics, one exhibiting epidermal progenitor cell hyperplasia with the other displaying a complete loss of epidermal tissue renewal indicating deregulation of stem cell activity. These data suggest that correct temporal regulation of hedgehog activity is a key factor in ensuring epidermal stem cell maintenance. In addition, we observed Shh and Dhh transgenic skin from both phenotypes developed lesions reminiscent of human basal cell carcinoma (BCC), indicating that BCCs can be generated despite the loss of much of the proliferative (basal) compartment. These data suggest the intriguing possibility that BCC can arise outside the stem cell population. Thus the elucidation of Shh (and Dhh)target gene activation in the skin will likely identify those genes responsible for increasing the proliferative potential of epidermal basal cells and the mechanisms involved in regulating epidermal stem cell fate.<\/jats:p>","DOI":"10.1242\/dev.01367","type":"journal-article","created":{"date-parts":[[2004,9,16]],"date-time":"2004-09-16T00:12:45Z","timestamp":1095293565000},"page":"5009-5019","source":"Crossref","is-referenced-by-count":88,"title":["An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis"],"prefix":"10.1242","volume":"131","author":[{"given":"Christelle","family":"Adolphe","sequence":"first","affiliation":[{"name":"Institute for Molecular Bioscience, and Special Research Centre for Functional and Applied Genomics, University of Queensland, and the Cooperative Research Centre for the Discovery of Genes for Common Human Diseases, Victoria,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Narang","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, and Special Research Centre for Functional and Applied Genomics, University of Queensland, and the Cooperative Research Centre for the Discovery of Genes for Common Human Diseases, Victoria,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammy","family":"Ellis","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, and Special Research Centre for Functional and Applied Genomics, University of Queensland, and the Cooperative Research Centre for the Discovery of Genes for Common Human Diseases, Victoria,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Wicking","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, and Special Research Centre for Functional and Applied Genomics, University of Queensland, and the Cooperative Research Centre for the Discovery of Genes for Common Human Diseases, Victoria,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pritinder","family":"Kaur","sequence":"additional","affiliation":[{"name":"Epithelial Stem Cell Biology Laboratory, Peter MacCallum Cancer Institute,Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Wainwright","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, and Special Research Centre for Functional and Applied Genomics, University of Queensland, and the Cooperative Research Centre for the Discovery of Genes for Common Human Diseases, Victoria,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042612004219000_REF1","doi-asserted-by":"crossref","unstructured":"Albert, M. R., Foster, R. A. and Vogel, J. C.(2001). Murine epidermal label-retaining cells isolated by flow cytometry do not express the stem cell markers CD34, Sca-1, or Flk-1. J. Invest. Dermatol.117,943-948.","DOI":"10.1046\/j.0022-202x.2001.01517.x"},{"key":"2021042612004219000_REF2","doi-asserted-by":"crossref","unstructured":"Bickenbach, J. R. and Chism, E. (1998). Selection and extended growth of murine epidermal stem cells in culture. Exp. Cell Res.244,184-195.","DOI":"10.1006\/excr.1998.4163"},{"key":"2021042612004219000_REF3","doi-asserted-by":"crossref","unstructured":"Carpenter, D., Stone, D. M., Brush, J., Ryan, A., Armanini, M.,Frantz, G., Rosenthal, A. and de Sauvage, F. J. (1998). Characterization of two patched receptors for the vertebrate hedgehog protein family. Proc. Natl. Acad. Sci. USA95,13630-13634.","DOI":"10.1073\/pnas.95.23.13630"},{"key":"2021042612004219000_REF4","unstructured":"Chiang, C., Swan, R. Z., Grachtchouk, M., Bolinger, M.,Litingtung, Y., Robertson, E. K., Cooper, M. K., Gaffield, W., Westphal, H.,Beachy, P. A. et al. (1999). Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev. Biol.205,1-9."},{"key":"2021042612004219000_REF5","doi-asserted-by":"crossref","unstructured":"Dellavalle, R. P., Walsh, P., Marchbank, A., Grayson, T. E., Su,L. J., Parker, E. R., DeGregori, J., Penheiter, K., Aszterbaum, M., Epstein,E. H., Jr et al. (2002). CUSP\/p63 expression in basal cell carcinoma. Exp. Dermatol.11,203-208.","DOI":"10.1034\/j.1600-0625.2002.110302.x"},{"key":"2021042612004219000_REF6","doi-asserted-by":"crossref","unstructured":"Ellis, T., Smyth, I., Riley, E., Bowles, J., Adolphe, C.,Rothnagel, J. A., Wicking, C. and Wainwright, B. J. (2003). Overexpression of Sonic Hedgehog suppresses embryonic hair follicle morphogenesis. Dev. Biol.263,203-215.","DOI":"10.1016\/S0012-1606(03)00394-4"},{"key":"2021042612004219000_REF7","doi-asserted-by":"crossref","unstructured":"Fan, H. and Khavari, P. A. (1999). Sonic hedgehog opposes epithelial cell cycle arrest. J. Cell Biol.147,71-76.","DOI":"10.1083\/jcb.147.1.71"},{"key":"2021042612004219000_REF8","doi-asserted-by":"crossref","unstructured":"Fan, H., Oro, A. E., Scott, M. P. and Khavari, P. A.(1997). Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog. Nat. Med.3, 788-792.","DOI":"10.1038\/nm0797-788"},{"key":"2021042612004219000_REF9","doi-asserted-by":"crossref","unstructured":"Grachtchouk, V., Grachtchouk, M., Lowe, L., Johnson, T., Wei,L., Wang, A., de Sauvage, F. and Dlugosz, A. A. (2003). The magnitude of hedgehog signaling activity defines skin tumor phenotype. EMBO J.22,2741-2751.","DOI":"10.1093\/emboj\/cdg271"},{"key":"2021042612004219000_REF10","doi-asserted-by":"crossref","unstructured":"Hager, B., Bickenbach, J. R. and Fleckman, P.(1999). Long-term culture of murine epidermal keratinocytes. J. Invest. Dermatol.112,971-976.","DOI":"10.1046\/j.1523-1747.1999.00605.x"},{"key":"2021042612004219000_REF11","doi-asserted-by":"crossref","unstructured":"Hahn, H., Christiansen, J., Wicking, C., Zaphiropoulos, P. G.,Chidambaram, A., Gerrard, B., Vorechovsky, I., Bale, A. E., Toftgard, R.,Dean, M. et al. (1996). A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. J. Biol. Chem.271,12125-12128.","DOI":"10.1074\/jbc.271.21.12125"},{"key":"2021042612004219000_REF12","doi-asserted-by":"crossref","unstructured":"Janes, S. M., Lowell, S. and Hutter, C. (2002). Epidermal stem cells. J. Pathol.197,479-491.","DOI":"10.1002\/path.1156"},{"key":"2021042612004219000_REF13","doi-asserted-by":"crossref","unstructured":"Jones, P. H. and Watt, F. M. (1993). Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell73,713-724.","DOI":"10.1016\/0092-8674(93)90251-K"},{"key":"2021042612004219000_REF14","doi-asserted-by":"crossref","unstructured":"Karlsson, L., Bondjers, C. and Betsholtz, C.(1999). Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle. Development126,2611-2621.","DOI":"10.1242\/dev.126.12.2611"},{"key":"2021042612004219000_REF15","doi-asserted-by":"crossref","unstructured":"Kaur, P. and Li, A. (2000). Adhesive properties of human basal epidermal cells: an analysis of keratinocyte stem cells,transit amplifying cells, and postmitotic differentiating cells. J. Invest. Dermatol.114,413-420.","DOI":"10.1046\/j.1523-1747.2000.00884.x"},{"key":"2021042612004219000_REF16","doi-asserted-by":"crossref","unstructured":"Kinto, N., Iwamoto, M., Enomoto-Iwamoto, M., Noji, S., Ohuchi,H., Yoshioka, H., Kataoka, H., Wada, Y., Yuhao, G., Takahashi, H. E. et al. (1997). Fibroblasts expressing Sonic hedgehog induce osteoblast differentiation and ectopic bone formation. FEBS Lett404,319-323.","DOI":"10.1016\/S0014-5793(97)00014-8"},{"key":"2021042612004219000_REF17","doi-asserted-by":"crossref","unstructured":"Koster, M. I. and Roop, D. R. (2004). The role of p63 in development and differentiation of the epidermis. J. Dermatol. Sci.34,3-9.","DOI":"10.1016\/j.jdermsci.2003.10.003"},{"key":"2021042612004219000_REF18","doi-asserted-by":"crossref","unstructured":"Legg, J., Jensen, U. B., Broad, S., Leigh, I. and Watt, F. M. (2003). Role of melanoma chondroitin sulphate proteoglycan in patterning stem cells in human interfollicular epidermis. Development130,6049-6063.","DOI":"10.1242\/dev.00837"},{"key":"2021042612004219000_REF19","doi-asserted-by":"crossref","unstructured":"Li, A., Simmons, P. J. and Kaur, P. (1998). Identification and isolation of candidate human keratinocyte stem cells based on cell surface phenotype. Proc. Natl. Acad. Sci. USA95,3902-3907.","DOI":"10.1073\/pnas.95.7.3902"},{"key":"2021042612004219000_REF20","doi-asserted-by":"crossref","unstructured":"Machold, R., Hayashi, S., Rutlin, M., Muzumdar, M. D., Nery, S.,Corbin, J. G., Gritli-Linde, A., Dellovade, T., Porter, J. A., Rubin, L. L. et al. (2003). Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron39,937-950.","DOI":"10.1016\/S0896-6273(03)00561-0"},{"key":"2021042612004219000_REF21","doi-asserted-by":"crossref","unstructured":"Mayumi, H., Nomoto, K. and Good, R. A. (1988). A surgical technique for experimental free skin grafting in mice. Jpn. J. Surg.18,548-557.","DOI":"10.1007\/BF02471489"},{"key":"2021042612004219000_REF22","unstructured":"McKeon, F. (2004). p63 and the epithelial stem cell: more than status quo? Genes Dev.18,465-469."},{"key":"2021042612004219000_REF23","doi-asserted-by":"crossref","unstructured":"Mills, A. A., Zheng, B., Wang, X. J., Vogel, H., Roop, D. R. and Bradley, A. (1999). p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature398,708-713.","DOI":"10.1038\/19531"},{"key":"2021042612004219000_REF24","unstructured":"Morgan, B. A., Orkin, R. W., Noramly, S. and Perez, A.(1998). Stage-specific effects of sonic hedgehog expression in the epidermis. Dev. Biol.201, 1-12."},{"key":"2021042612004219000_REF25","doi-asserted-by":"crossref","unstructured":"Niemann, C., Unden, A. B., Lyle, S., Zouboulis Ch, C., Toftgard,R. and Watt, F. M. (2003). Indian hedgehog and beta-catenin signaling: role in the sebaceous lineage of normal and neoplastic mammalian epidermis. Proc. Natl. Acad. Sci. USA100 Suppl. 1,11873-11880.","DOI":"10.1073\/pnas.1834202100"},{"key":"2021042612004219000_REF26","doi-asserted-by":"crossref","unstructured":"Oro, A. E. and Higgins, K. (2003). Hair cycle regulation of Hedgehog signal reception. Dev. Biol.255,238-248.","DOI":"10.1016\/S0012-1606(02)00042-8"},{"key":"2021042612004219000_REF27","doi-asserted-by":"crossref","unstructured":"Oro, A. E., Higgins, K. M., Hu, Z., Bonifas, J. M., Epstein Jr,E. H. and Scott, M. P. (1997). Basal cell carcinomas in mice overexpressing Sonic hedghog. Science276,817-821.","DOI":"10.1126\/science.276.5313.817"},{"key":"2021042612004219000_REF28","doi-asserted-by":"crossref","unstructured":"Palma, V. and Ruiz i Altaba, A. (2004). Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development131,337-345.","DOI":"10.1242\/dev.00930"},{"key":"2021042612004219000_REF29","doi-asserted-by":"crossref","unstructured":"Pathi, S., Pagan-Westphal, S., Baker, D. P., Garber, E. A.,Rayhorn, P., Bumcrot, D., Tabin, C. J., Blake Pepinsky, R. and Williams, K. P. (2001). Comparative biological responses to human Sonic,Indian, and Desert hedgehog. Mech. Dev.106,107-117.","DOI":"10.1016\/S0925-4773(01)00427-0"},{"key":"2021042612004219000_REF30","doi-asserted-by":"crossref","unstructured":"Pellegrini, G., Dellambra, E., Golisano, O., Martinelli, E.,Fantozzi, I., Bondanza, S., Ponzin, D., McKeon, F. and De Luca, M.(2001). p63 identifies keratinocyte stem cells. Proc. Natl. Acad. Sci. USA98,3156-3161.","DOI":"10.1073\/pnas.061032098"},{"key":"2021042612004219000_REF31","doi-asserted-by":"crossref","unstructured":"Sato, N., Leopold, P. L. and Crystal, R. G.(1999). Induction of the hair growth phase in postnatal mice by localized transient expression of Sonic hedgehog. J. Clin. Invest.104,855-864.","DOI":"10.1172\/JCI7691"},{"key":"2021042612004219000_REF32","unstructured":"Sheng, H., Goich, S., Wang, A., Grachtchouk, M., Lowe, L., Mo,R., Lin, K., de Sauvage, F. J., Sasaki, H., Hui, C. C. et al.(2002). Dissecting the oncogenic potential of Gli2: deletion of an NH(2)-terminal fragment alters skin tumor phenotype. Cancer Res.62,5308-5316."},{"key":"2021042612004219000_REF33","doi-asserted-by":"crossref","unstructured":"St-Jacques, B., Dassule, H. R., Karavanova, I., Botchkarev, V. A., Li, J., Danielian, P. S., McMahon, J. A., Lewis, P. M., Paus, R. and McMahon, A. P. (1998). Sonic hedgehog signaling is essential for hair development. Curr. Biol.8,1058-1068.","DOI":"10.1016\/S0960-9822(98)70443-9"},{"key":"2021042612004219000_REF34","doi-asserted-by":"crossref","unstructured":"Taipale, J. and Beachy, P. (2001). The Hedgehog and Wnt signalling pathways in cancer. Nature17,349-354.","DOI":"10.1038\/35077219"},{"key":"2021042612004219000_REF35","doi-asserted-by":"crossref","unstructured":"Tani, H., Morris, R. J. and Kaur, P. (2000). Enrichment for murine keratinocyte stem cells based on cell surface phenotype. Proc. Natl. Acad. Sci. USA97,10960-10965.","DOI":"10.1073\/pnas.97.20.10960"},{"key":"2021042612004219000_REF36","unstructured":"Trempus, C. S., Morris, R. J., Bortner, C. D., Cotsarelis, G.,Faircloth, R. S., Reece, J. M. and Tennant, R. W. (2003). Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J. Invest. Dermatol.120,501-511."},{"key":"2021042612004219000_REF37","doi-asserted-by":"crossref","unstructured":"Vortkamp, A., Lee, K., Lanske, B., Segre, G. V., Kronenberg, H. M. and Tabin, C. J. ( 1996). Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science273,613-622.","DOI":"10.1126\/science.273.5275.613"},{"key":"2021042612004219000_REF38","doi-asserted-by":"crossref","unstructured":"Weedon, D. (1981). Elastotic nodules of the ear. J. Cutaneous Pathol.8, 429-433.","DOI":"10.1111\/j.1600-0560.1981.tb01032.x"},{"key":"2021042612004219000_REF39","doi-asserted-by":"crossref","unstructured":"Xie, J., Murone, M., Luoh, S. M., Ryan, A., Gu, Q., Zhang, C.,Bonifas, J. M., Lam, C. W., Hynes, M., Goddard, A. et al.(1998). Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature391,90-92.","DOI":"10.1038\/34201"},{"key":"2021042612004219000_REF40","doi-asserted-by":"crossref","unstructured":"Yang, A., Schweitzer, R., Sun, D., Kaghad, M., Walker, N.,Bronson, R. T., Tabin, C., Sharpe, A., Caput, D., Crum, C. et al.(1999). p63 is essential for regenerative proliferation in limb,craniofacial and epithelial development. Nature398,714-718.","DOI":"10.1038\/19539"},{"key":"2021042612004219000_REF41","doi-asserted-by":"crossref","unstructured":"Zhang, Y. and Kalderon, D. (2001). Hedgehog acts as a somatic stem cell factor in the Drosophila ovary. 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