A Signaling Pathway Involving TGF-β2 and Snail in Hair Follicle Morphogenesis

Abstract

In a common theme of organogenesis, certain cells within a multipotent epithelial sheet exchange signals with their neighbors and develop into a bud structure. Using hair bud morphogenesis as a paradigm, we employed mutant mouse models and cultured keratinocytes to dissect the contributions of multiple extracellular cues in orchestrating adhesion dynamics and proliferation to shape the cluster of cells involved. We found that transforming growth factor β2 signaling is necessary to transiently induce the transcription factor Snail and activate the Ras-mitogen-activated protein kinase (MAPK) pathway in the bud. In the epidermis, Snail misexpression leads to hyperproliferation and a reduction in intercellular adhesion. When E-cadherin is transcriptionally down-regulated, associated adhesion proteins with dual functions in signaling are released from cell-cell contacts, a process which we demonstrate leads to Ras-MAPK activation. These studies provide insights into how multipotent cells within a sheet are stimulated to undergo transcriptional changes that result in proliferation, junctional remodeling, and bud formation. This novel signaling pathway further weaves together the web of different morphogens and downstream transcriptional events that guide hair bud formation within the developing skin.

Laminin-511 is an epithelial message promoting dermal papilla development and function during early hair morphogenesis

“…Selective down-regulation of E-cadherin but not P-cadherin is a crucial step in hair follicle downgrowth (Jamora et al 2005). Consistent with our observed defect of Lef-1 activity, we found a conspicuous lack of E-cadherin down-regulation in follicular epithelium in lama5 −/− skin at E16.5, despite unaffected Pcadherin expression (Fig.…”

Epidermal Snail expression drives skin cancer initiation and progression through enhanced cytoprotection, epidermal stem/progenitor cell expansion and enhanced metastatic potential

“…Sustained Snail expression in the basal layer of the skin leads to epidermal hyperproliferation resulting in increased epidermal thickness in K14-Snail mice. 12 Quantification of Ki-67-positive cells in Snail-positive skin further supports this enhanced proliferation rate (Figures 1a and b).…”

“…11 To gain further insight into the specific in vivo role of Snail during skin cancer progression, we used a combined immunohistochemical analysis of a variety of human skin cancers along with a mouse model with skin-specific expression of an HA-tagged Snail protein. 12 Here we report for the first time that Snail transgenic mice develop spontaneous tumours: our results indicate that enhanced Snail expression contributes to the stabilisation, expansion and survival of skin stem cells in vivo, which can result in both skin tumour initiation and malignant progression for a variety of epithelialderived tumour types.…”

Expression of Snail protein in tumor–stroma interface

“…Recently, Snail has been shown to play a role in the cutaneous hair follicle morphogenesis (Jamora et al, 2005). Using our MAb, immunoreactivity for Snail was detected in dermal mesenchymal cells adjacent to the hair bud (dermal condensate) but not in the epithelial cells (Figure 2h).…”