Canonical Wnt signaling negatively regulates branching morphogenesis of the lung and lacrimal gland

Key gene families such as FGFs and BMPs are important mediators of branching morphogenesis. To understand whether Writ genes, and in particular, the canonical Writ signaling pathway also function in the branching process, we have used a combination of experimental and genetic gain and loss of function approaches to perturb the levels of canonical Writ signaling in two arborized structures, the lung and the lacrimal gland. Here, we show that the addition of Wnt3a conditioned medium or LiCl strongly represses growth and proliferation of the lung and lacrimal gland, a result that was confirmed in vivo using a dominant stable mutation of beta-catenin conditionally expressed in the lacrimal gland epithelium. In agreement with these data, knockdown of Writ signaling with beta-catenin morpholmos results in a greater number of branches and increased cell proliferation. In addition, we show that canonical Writ signaling is able to triodulate the levels of Fgf10 and suppress BMP-induced proliferation in the lacrimal gland. Thus, canonical Writ signaling negatively regulates branching morphogenesis providing a balance to FGFs and BMPs which positively regulate this process. This multilayered control of growth and proliferation ensures that branched structures attain the morphology required to function efficiently. (c) 2005 Elsevier Inc. All rights reserved.