The Wingless / wnt signalling pathway in the development of murine hair follicles

Petter Portin

The wingless / wnt signalling pathway is a very interesting example of the many cell-cell signalling systems, first demonstrated in the fruit fly Drosophila melanogaster, and possibly conserved throughout the whole animal kingdom.

In fly development at the stage of segmental definition, the cells that define the boundaries of the anterior and posterior compartments express wingless (Wg) and engrailed (En) in a reciprocal relationship. The wingless signalling pathway causes engrailed gene to be expressed. Engrailed causes the production of hedgehog (Hg) protein, which in turn is secreted. Hedgehog acts on the cell on its anterior side to maintain wingless expression. Wg is also required for patterning of adult eyes, legs, and wings (hence its name).

Porc (coded by porcupine) is a trans-membrane protein that is required to assist the secretion of Wg from the anterior cell. The receptor for Wg in Drosophila melanogaster on the posterior cell is most likely the frizzle-related protein, DFz2 (Drosophila frizzled-2).

The pathway in vertebrate cells is basically the same. The ligands that trigger the pathway are members of the Wnt protein family which has approximately 8 members and are glycoproteins related to Wg. Different members of the Wnt family are expressed in different times and places in the vertebrate embryo, where the pathway is involved in patterning events. One example is that the Niewkoop centre triggers a Wnt pathway with the effect of inducing the Spemann organiser. Thus, actually the Wnt protein family in vertebrates is involved in the development of ectoderm (e.g. epithelium) and mesoderm (e.g. mesenchyme) during morphogenesis.

The hair follicle on its part presents an attractive experimental system to study epithelial-mesenchymal interactions. In a recent issue of Genes & Development (14: 1181 - 1185, 2000) Jiro Kishimoto et al. have used this system to investigate the role of Wnt proteins in murine development.

The adult hair follicle undergoes a cycle of hair growth (anagen) followed by a regression phase (catagen), a quiescent phase (telogen), and re-entry into anagen to generate a new hair shaft in the existing follicle. The hair shaft is derived from the epithelial matrix cells at the base of the follicle. However, a cluster of dermal cells ensheathed by the matrix cells, known as dermal papilla (DP), is thought to supply an inductive signal required for hair outgrowth.

Already (Proc. Natl. Acad. Sci. USA 96: 7336 - 7341, 1999) Kishimoto et al. have shown in a transgenic mouse line that expresses green fluorescent protein (GFP) in the DP cells that the transgene is active during anagen but is shut off during catagen and telogen. Thus, the expression of the transgene correlates with the presumed profile of the inductive activity in the DP. However, this inductive activity and GFP expression were rapidly lost in culture, suggesting that a factor normally supplied by epidermal cells is required to maintain DP cells in the anagen state. In the work reported now, Kishimoto et al. examined the ability of signalling molecules that are expressed in the follicular epithelium to maintain isolated DP cells in an active, anagen state. In their analysis Kishimoto et al. were able to show that specific members of the Wnt protein family, but not Sonic hedgehog (The vertebrate homologue of the hedgehog gene of the fruit fly), maintain anagen-phase gene expression in vitro and hair inductive activity in a skin reconstitution assay. The Wnts do this most likely by serving as a signal from the epidermis to activate gene expression in the DP. Thus, the findings demonstrate a role for Wnts in signalling to the DP. Moreover, Kishimoto et al. suggested that a single particular Wnt expressed in the epidermis could co-ordinate development in both the dermis and epidermis.