Overexpression of Sonic Hedgehog suppresses embryonic hair follicle morphogenesis

Abstract

The Sonic Hedgehog (Shh) signalling pathway plays a central role in the development of the skin and hair follicle and is a major determinant of skin tumorigenesis, most notably of basal cell carcinoma (BCC). Various mouse models involving either ablation or overexpression of key members of the Shh signalling pathway display a range of skin tumours. To further examine the role of Shh in skin development, we have overexpressed Shh in a subset of interfollicular basal cells from 12.5 dpc under the control of the human keratin 1 (HK1) promoter. The HK1-Shh transgenic mice display a range of skin anomalies, including highly pigmented inguinal lesions and regions of alopecia. The most striking hair follicle phenotype is a suppression in embryonic follicle development between 14.0 and 19.0 dpc, resulting in a complete absence of guard, awl, and auchene hair fibres. These data indicate that alternative signals are responsible for the development of different hair follicles and point to a major role of Shh signalling in the morphogenesis of guard, awl, and auchene hair fibres. Through a comparison with other mouse models, the characteristics of the HK1-Shh transgenic mice suggest that the precise timing and site of Shh expression are key in dictating the resultant skin and tumour phenotype.

Epidermal differentiation complex (locus 1q21) gene expression in head and neck cancer and normal mucosa

“…It has to be stressed that the proteins originating from the complex structure of skin layers and regulating its keratinization may behave differently in various contexts [60,61]. When we compared our data with the analysis of Hudson et al, who suggested that coordinated over-expression of EDC genes is a hallmark of skin squamous cell carcinoma, we reached similar global conclusions [15].…”

An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis

“…However, we have recently shown that overexpression of hedgehog in only a subset of basal cells, using the human K1 promoter (hK1), results in the ablation of embryonic hair follicle development and does not give rise to BCC (Ellis et al, 2003). The overexpression of hedgehog via the hK1 promoter drives hedgehog activity in committed epidermal cells, thus only in a small subset (20-30%) of basal cells, the PMDpopulation.…”

Transcriptome and phenotypic analysis reveals Gata3-dependent signalling pathways in murine hair follicles

“…In addition, increased or reduced expression levels for certain genes, including Hoxc13 (Godwin and Capecchi, 1998;Tkatchenko et al, 2001), BMP genes (Blessing et al, 1996;Botchkarev et al, 2002) and Notch1 (Uyttendaele et al, 2004;Vauclair et al, 2005), associated with the signaling mechanisms in hair formation appear to exert similar effects. However, for the majority of genes, it becomes increasingly apparent that their exact temporal and spatial expression is crucial; whereas reduction in Shh expression levels results in disturbed HF growth (St-Jacques et al, 1998), its increase leads to epidermal hyper-proliferation with distinct phenotypic features (Ellis et al, 2003).…”