Indian hedgehog and β-catenin signaling: Role in the sebaceous lineage of normal and neoplastic mammalian epidermis

doi:10.1073/pnas.1834202100

Indian hedgehog and β-catenin signaling: Role in the sebaceous lineage of normal and neoplastic mammalian epidermis

^†Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom; ^‡Department of Biosciences at Novum, Karolinska Institutet, SE-141 57 Huddinge, Sweden; ^§Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and ^¶Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, 14195 Berlin, Germany

Abstract

In mammalian epidermis, the level of β-catenin signaling regulates lineage selection by stem cell progeny. High levels of β-catenin stimulate formation of hair follicles, whereas low levels favor differentiation into interfollicular epidermis and sebocytes. In transgenic mouse epidermis, overexpression of β-catenin leads to formation of hair follicle tumors, whereas overexpression of N-terminally truncated Lef1, which blocks β-catenin signaling, results in spontaneous sebaceous tumors. Accompanying overexpression of β-catenin is up-regulation of Sonic hedgehog (SHH) and its receptor, Patched (PTCH/Ptch). In ΔNLef1 tumors Ptch mRNA is up-regulated in the absence of SHH. We now show that PTCH is up-regulated in both human and mouse sebaceous tumors and is accompanied by overexpression of Indian hedgehog (IHH). In normal sebaceous glands IHH is expressed in differentiated sebocytes and the transcription factor GLI1 is activated in sebocyte progenitors, suggesting a paracrine signaling mechanism. PTCH1 and IHH are up-regulated during human sebocyte differentiation in vitro and inhibition of hedgehog signaling inhibits growth and stimulates differentiation. Overexpression of ΔNLef1 up-regulates IHH and stimulates proliferation of undifferentiated sebocytes. We present a model of the interactions between β-catenin and hedgehog signaling in the epidermis in which SHH promotes proliferation of progenitors of the hair lineages whereas IHH stimulates proliferation of sebocyte precursors.

Footnotes

↵ ∥ To whom correspondence should be addressed. E-mail: fiona.watt{at}cancer.org.uk.
↵ * C.N. and A.B.U. contributed equally to this work.
This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, “Regenerative Medicine,” held October 18-22, 2002, at the Arnold and Mabel Beckman Center of the National Academies of Science and Engineering in Irvine, CA.
Abbreviations: Hh, hedgehog; DHH, Desert Hh; IHH, Indian Hh; SHH, Sonic Hh; PTCH/Ptch, Patched; IFE, interfollicular epidermis; BCC, basal cell carcinoma.