Epidermal Notch signalling: differentiation, cancer and adhesion

Abstract

The Notch pathway plays an important role in regulating epidermal differentiation. Notch ligands, receptors and effectors are expressed in a complex and dynamic pattern in embryonic and adult skin. Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages and that Notch acts as an epidermal tumour suppressor. Notch signalling interacts with a range of other pathways to fulfil these functions and acts via RBP-Jkappa dependent and independent mechanisms. The effects on differentiation can be cell autonomous and non-autonomous, and Notch contributes to stem cell clustering via modulation of cell adhesion.

Figure 1

The core Notch signalling pathway. ICD: intracellular domain; MAML: Mastermind-like. Based on reference [4].

Figure 2

Expression of Notch ligands and receptors. Neonatal interfollicular epidermis (top panel) and hair follicles (bottom panel) are shown. Hatched shading indicates co-expression. CL: cornified layer; GL: granular layer; SL: spinous layer. Adapted from references [7^••,11].

Figure 3

Model showing cell autonomous and non-cell autonomous roles of Dll1 in human IFE reconstituted in culture. Reproduced from reference [40^••] with permission of the Company of Biologists. Keratinocytes are shown as wild type (WT) or overexpressing full-length Dll1 (Fl), Dll1 lacking the cytoplasmic domain (DS) or Dll1 with a point mutation in the C-terminal PDZ domain (VA). The symbol (←) represents signal from Delta-expressing cell to wild-type cell; the symbol (↔) represents reciprocal signalling between two Delta-expressing cells. The strength of the differentiation signal is represented by the thickness of the vertical arrows. Intercellular adhesion (cohesion) is shown as being promoted (arrow) or not (cross through arrow).

Figure 4

Requirement of Jagged1 for induction of ectopic hair follicles by β-catenin. Reproduced from reference [14^••] with permission of the Company of Biologists. Activation of β-catenin in a wild-type background (βcatER) induces ectopic hair follicle formation (arrows) and stimulates growth (anagen) of existing hair follicles. Anagen and ectopic hair follicle formation are blocked by epidermal deletion of Jagged1 (β-catER × Jag1^−/−). The control is back skin from a Jag1 flox/flox mouse. Scale bar: 100 μm.