Getting to the root of the problem

Signals that are transmitted through cell junctions can transform epithelial layers into three-dimensional structures such as hair follicles. Desmosomes, which are specialized cell junctions that make up much of the cell surfaces in mature hair follicles, contribute — in part through desmosomal cadherins — to cell–cell adhesion. Kljuic et al., reporting in Cell, have identified desmoglein 4 and report its function in epidermal adhesion and hair-follicle differentiation.

None of the known desmosomal cadherins are expressed in the inner layers of the hair shaft despite the abundance of desmosomes here. So the authors carried out a classical genetic approach using patients with localized autosomal-recessive hypotrichosis (LAH), a condition in which hair is less dense, and located a candidate gene close to a desmosomal cadherin gene cluster.

Further analysis showed synteny with the mouse lanceolate hair (lah) mutation — which impairs hair growth — which is also near the desmosomal cadherin gene cluster. During this genomic analysis, a previously uncharacterized cadherin gene — designated desmoglein 4 (Dsg4) — was identified in the cluster. Desmoglein 4 was highly expressed in human and mouse skin, and colocalized with the lah and LAH linkage intervals, making Dsg4 a candidate for both phenotypes. The authors then showed Dsg4 to be mutated in LAH humans and lah mice. A second lah allele, lah^J, causes a more severe phenotype, and further sequence analysis showed that lah^J/lah^J mice are null (lah/lah mice are hypomorphic).

Dsg4 was shown to be the main desmosomal cadherin in hair follicles, and analysis of the epidermis and hair follicles from lah^J/lah^J-mutant pups showed that Dsg4 had a central role in cell–cell adhesion — desmosomes were sparse, poorly formed and often detached or torn away from their neighbours. Kljuic et al. then proposed, when assaying the expression of several epidermal markers, that the keratinocytes of lah^J/lah^J mice exited the basal compartment of the epidermis — in which keratinocytes proliferate — earlier or faster than normal, thereby expanding the proliferative compartment. Indeed, ectopically proliferating cells were found in the suprabasal layers, as shown by the expression of β1 integrin and the epidermal growth factor receptor (EGFR). In the context of lah mutants, this increased expression of β1 and EGFR correlated with enhanced keratinocyte–substrate adhesion and spreading in vitro.

In wild-type hair formation, keratinocytes in the lowest part of the hair follicle proliferate rapidly until they pass through a 'critical region', in which mitosis stops and the cells start to differentiate. The transition through the critical region is usually gradual, but lah^J/lah^J-mutant hair follicles abruptly stop proliferating and start differentiating. The authors propose that this abrupt transition might arise from, or be precipitated by, the defective cell–cell adhesion that impairs the transduction of signals that are important in survival and the full execution of cell-fate determination.

This is one of the first reports of a defect in a structural component — Dsg4 — of the epidermis and hair follicle that causes corresponding mouse and human phenotypes. In addition, as the authors also showed that Dsg4 functions as an autoantigen in patients with pemphigus vulgaris (an autoimmune skin disease characterized by outbreaks of blisters), the relevance of the findings extends to skin autoimmunity.