WNT signaling in the control of hair growth and structure

Characterization of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles is central to our understanding o f the regulation of normal hair growth, the basis of hereditary hair loss d iseases, and the origin of follicle-based tumors. We demonstrate that the p roto-oncogene Wnt3, which encodes a secreted paracrine signaling molecule, is expressed in developing and mature hair follicles and that its overexpre ssion in transgenic mouse skin causes a short-hair phenotype due to altered differentiation of hair shaft precursor cells, and cyclical balding result ing from hair shaft structural defects and associated with an abnormal prof ile of protein expression in the hair shaft. A putative effector molecule f or WNT3 signaling, the cytoplasmic protein Dishevelled 2 (DVL2), is normall y present at high levels in a subset of cells in the outer root sheath and in precursor cells of the hair shaft cortex and cuticle which lie immediate ly adjacent to Wnt3-expressing cells. Overexpression of Dvl2 in the outer r oot sheath mimics the short-hair phenotype produced by overexpression of Wn t3, supporting the hypothesis that Wnt3 and Dvl2 have the potential to act in the same pathway in the regulation of hair growth. These experiments dem onstrate a previously unrecognized role for WNT signaling in the control of hair growth and structure, as well as presenting the first example of a ma mmalian phenotype resulting from overexpression of a Dvl gene and providing an accessible in vivo system for analysis of mammalian WNT signaling pathw ays. (C) 1999 Academic Press.