WNT Signaling in the Control of Hair Growth and Structure

Abstract

Characterization of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles is central to our understanding of the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. We demonstrate that the proto-oncogene Wnt3, which encodes a secreted paracrine signaling molecule, is expressed in developing and mature hair follicles and that its overexpression in transgenic mouse skin causes a short-hair phenotype due to altered differentiation of hair shaft precursor cells, and cyclical balding resulting from hair shaft structural defects and associated with an abnormal profile of protein expression in the hair shaft. A putative effector molecule for WNT3 signaling, the cytoplasmic protein Dishevelled 2 (DVL2), is normally 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 immediately adjacent to Wnt3-expressing cells. Overexpression of Dvl2 in the outer root sheath mimics the short-hair phenotype produced by overexpression of Wnt3, supporting the hypothesis that Wnt3 and Dvl2 have the potential to act in the same pathway in the regulation of hair growth. These experiments demonstrate a previously unrecognized role for WNT signaling in the control of hair growth and structure, as well as presenting the first example of a mammalian phenotype resulting from overexpression of a Dvl gene and providing an accessible in vivo system for analysis of mammalian WNT signaling pathways.

An Unconventional Nuclear Localization Motif Is Crucial for Function of the Drosophila Wnt/Wingless Antagonist Naked Cuticle

“…Our finding that nkd mutants have elevated Arm/b-catenin levels concomitant with broadened domains of Wg target gene expression is consistent with prior reports of Nkd targeting Dsh, an enigmatic Wnt signal transducer that acts upstream of b-catenin degradation. Although Wnt-signal-induced Dsh accumulation has been observed in cultured cells (Yanagawa et al 1995), transgenic mice (Millar et al 1999), and some cancers (Uematsu et al 2003), and recent studies indicate that Dsh, like b-catenin, can be degraded by the ubiquitin-proteasome pathway (Simons et al 2005;Angers et al 2006;Zhang et al 2006), our data show that Nkd does not attenuate Wnt signaling in the embryo by significantly altering steady-state Dsh levels or distribution. If Nkd promotes Dsh degradation in the fly embryo, as has recently been proposed on the basis of overexpression of mammalian Nkd in cultured cells (Creyghton et al 2005), it must act only on a subset Figure 9A as well as the C-terminal extent of constructs Nkd NIN3/GFPC and Nkd NIN4/GFPC (each named for the position of nkd intron 3 and 4, respectively).…”

Maintenance and Repair of the Bronchiolar Epithelium

“…Direct roles for Wnt/b-catenin in mediating these outcomes have been implied from studies involving genetically modified mouse models, for which potentiation or inhibition of b-catenin signaling leads to either expansion or regression of the proliferative compartment within intestinal crypts, respectively, and loss of differentiated intestinal epithelial cells (37,38). Potentiation of the Wnt/b-catenin pathway has similarly profound influences on the self-renewal capacity and differentiation potential of other stem cell hierarchies, such as those of the hematopoietic system (39)(40)(41)(42) or the epidermis (43)(44)(45)(46), leading in each case to expansion of the stem/progenitor cell pool and either arrested or altered differentiation. However, even though the Wnt/b-catenin pathway plays a critical role in regulation of lung development (47)(48)(49), it is unclear if it fulfills similar roles in the maintenance of adult lung stem cells.…”

Characterization of Wnt signaling components and activation of the Wnt canonical pathway in the murine retina

“…Notably, at E13.5, ␤-gal activity was localized to cells in the neuroblast layer close to the RPE, which correspond to the region where presumptive photoreceptors are localized, raising the possibility that Wnt signaling plays a role in photoreceptor development. Wnt-3, -5a, and -7b have been shown to play a role in precursor cell proliferation in several tissues including the limb, hair follicle, lung, and caudal regions of the embryo (McMahon et al, 1992;Gofflot et al, 1998;Millar et al, 1999;Yamaguchi et al, 1999;Reddy et al, 2001;Shu et al, 2002). Wnt-5b is expressed in the developing gut (Lickert et al, 2001); however, the function of Fig.…”