Wnt-responsive genes (blue) are not turned on in mice lacking BMP signaling (right).

Amorphogen must be both off and on for hairs to grow, according to Kobielak et al. on page 609. Their studies of bald mice reveal that bone morphogenetic protein (BMP) controls the switch from dividing to differentiating hair cells by working at the right time and place.

Hair cells arise from a pool of epithelial precursors that first proliferate and then differentiate to form the hair channel and the hair itself. Proliferation signals originate from a set of mesenchymal cells called the dermal papillae (DP) at the base of the hair follicle. Further up the follicle, differentiation is a response to Wnt signaling that works through stabilized β-catenin and Lef1 to turn on genes such as hair keratins. Now, Kobielak et al. find that the later differentiation depends on both the absence of BMP signaling during proliferation, which allows a buildup of Lef-1, and the presence of BMP signaling later on, which is somehow permissive for Wnt signaling once that pool of Lef-1 has accumulated.

Kobielak et al. tease out these functions by knocking out the BMP receptor 1A in the embryonic skin epithelium. The resulting hairless mice reveal that BMP signaling must first be off, and then on, for hairs to form. At the base of the mutant hair follicle, Lef1 was expressed in progenitor cells as expected. But these proliferating cells never differentiated. Although Lef1 was present further up the hair shaft, β-catenin was not stabilized and differentiation genes were not activated. The precise cause of the block is not known, but BMP signaling might activate Wnt receptors or inactivate the β-catenin degradation machinery.

The authors propose that BMPs control the timing of responses to Lef1 in the hair shaft. Progenitor cells have BMP receptors, but they are turned off by the BMP inhibitor Noggin secreted by the nearby DP. They therefore maintain an undifferentiated state while accumulating Lef1. As the proliferating cells move away from the source of Noggin, BMP receptors are activated, thus promoting Wnt signaling and differentiation. ▪