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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.

Sexual hormones are important in the maintenance of human skin. Being the endocrine“brain” of the skin, the sebaceous gland is a major target of sexual hormones. While androgens stimulate sebocyte proliferation, estrogens do not to affect sebaceous gland growth. Regarding differentiation, androgens are expected to stimulate and estrogens to suppress sebaceous lipid synthesis, while estrogens,in vivo, enhance sebaceous lipogenesis in aged skin. The latter results have been disputed by currentin vitrodata indicating no direct effect of sexual hormones on sebocyte differentiation. To elucidate these contradictions we have investigated possible pathways which may be used by sexual hormones to modulate sebocyte differentiation in vitro. It has been postulated that androgen induction of lipogenesis requires the concomitant presence of peroxisome proliferator-activated receptor(PPAR) ligands. We found that arachidonic acid(AA), the direct precursor of leukotriene B4, a natural PPARα ligand, and linoleic acid(LA), a natural PPARδ ligand, induce sebocyte enlargement, accumulation of lipid droplets in the cytoplasm, and nuclear fragmentation. The combined administration of testosterone and AA or LA slightly increased sebaceous lipogenesis. In contrast, synthetic PPAR ligands were unable to enhance sebaceous lipogenesis. Interestingly, AA synthesis in human sebocytes was significantly stimulated by the prostaglandins(PG) E2 andΔ15-J2. On the other hand, PPARγ expression was downregulated by the phytoestrogen genistein. Interestingly, 17β-estradiol has previously been shown to induce the metabolism of PGD2 toΔ12-PGJ2, a natural PPARγ ligand. In addition, we found that 17β-estradiol increases IGF-I synthesis(+28%) and down-regulates IGF-IR expression(−37 to−48%), whereas IGF-I significantly induces sebaceous lipogenesis. In conclusion, sexual hormones are not directly active but are likely to utilize complex mechanisms, including modified known pro-inflammatory pathways, to modulate sebocyte differentiation. [ABSTRACT FROM AUTHOR]