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

Abstract

In mammalian epidermis, the level of ␤-catenin signaling regulates lineage selection by stem cell progeny. High levels of ␤-catenin stimulate formation of hair follicles, whereas low levels favor differentiation into interfollicular epidermis and sebocytes. In transgenic mouse epidermis, overexpression of ␤-catenin leads to formation of hair follicle tumors, whereas overexpression of N-terminally truncated Lef1, which blocks ␤-catenin signaling, results in spontaneous sebaceous tumors. Accompanying overexpression of ␤-catenin is up-regulation of Sonic hedgehog (SHH) and its receptor, Patched (PTCH͞Ptch). In ⌬NLef1 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 ⌬NLef1 up-regulates IHH and stimulates proliferation of undifferentiated sebocytes. We present a model of the interactions between ␤-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.

Transient activation of β-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours

“…High β-catenin expression results in hair follicle type tumours (Gat et al, 1998;Chan et al, 1999) whereas inhibition of β-catenin signalling with ∆NLef1 leads to the formation of sebaceous tumours at high frequency Niemann et al, 2003). The tumours induced by sustained activation of ∆Nβ-cateninER were highly differentiated and resembled human trichofolliculomas, consistent with the earlier observations of Gat et al (Gat et al, 1998) and Chan et al (Chan et al, 1999).…”

Beyond acne: Current aspects of sebaceous gland biology and function

“…Among them, β-catenin, transcription factor 3 (Tcf3) and lymphoid enhancer-binding factor-1 (Lef-1) seem to be of key importance. High levels of β-catenin stimulate the formation of hair follicles and low levels that of epidermis and sebaceous glands [29][30][31].. Lef-1 and Indian hedgehog (IHH) seem to cooperate to control proliferation and differentiation of sebocyte progenitors [32]. In contrast, SHH/Gli-signaling has been suggested to be specifically required for sebocyte development [33].…”

Role of FGFR2-signaling in the pathogenesis of acne

“…101 Within the epidermis Shh promotes proliferation of progenitors of hair lineages, whereas Indian hedgehog (Ihh) stimulates proliferation of sebocyte precursors. 102 Cleft palate and syndactyly are classical features of Apert syndrome. Inborn errors of cholesterol biosynthesis with decreased cholesterol and increased cholesterol precursors cause human malformation syndromes with facial malformations, cleft palate and syndactyly like in Apert syndrome.…”

“…102 They are able to produce IL-1α. 166 All layers of glandular and ductal cells of sebaceous glands were immunoreactive for both IL-1α and IL-1β.…”