Indian hedgehog and beta-catenin signaling: role in the sebaceous lineage of normal and neoplastic mammalian epidermis.
In mammalian epidermis, the level of beta-catenin signaling regulates lineage selection by stem cell progeny. High levels of beta-catenin stimulate formation of hair follicles, whereas low levels favor differentiation into interfollicular epidermis and sebocytes. In transgenic mouse epidermis, overexpression of beta-catenin leads to formation of hair follicle tumors, whereas overexpression of N-terminally truncated Lef1, which blocks beta-catenin signaling, results in spontaneous sebaceous tumors. Accompanying overexpression of beta-catenin is up-regulation of Sonic hedgehog (SHH) and its receptor, Patched (PTCH/Ptch). In DeltaNLef1 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 DeltaNLef1 up-regulates IHH and stimulates proliferation of undifferentiated sebocytes. We present a model of the interactions between beta-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.
Niemann
C
C
Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Unden
A B
AB
Lyle
S
S
Zouboulis
Ch C
ChC
Toftgård
R
R
Watt
F M
FM
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D018859:Hair Follicle / Q000166:cytology / Q000378:metabolism; D053823:Hedgehog Proteins; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D012626:Sebaceous Gland Neoplasms / Q000378:metabolism* / Q000473:pathology*; D012627:Sebaceous Glands / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C509239:SHH protein, human; C465570:Shh protein, mouse; D015534:Trans-Activators; D051176:beta Catenin