Alternative Wnt pathways and receptors

Abstract

In addition to activating β-catenin/TCF transcriptional complexes, Wnt proteins can elicit a variety of other responses. These are often lumped together under the denominator "alternative" or "non-canonical" Wnt signaling, but they likely comprise distinct signaling events. In this article, I discuss how the use of different ligand and receptor combinations is thought to give rise to these alternative Wnt-signaling responses. Although many of the biochemical details remain to be resolved, it is evident that alternative Wnt signaling plays important roles in regulating tissue morphogenesis during embryonic development.

Figure 1.

Planar cell polarity (PCP) as an example of alternative Wnt signaling. (A, top) PCP in the sensory epithelium of the mammalian cochlea manifests itself in the alignment of inner ear hair cells, which carry characteristic V-shaped stereociliary bundles of actin hairs on the apical cell surface (visualized here by phalloidin staining in red; kinocilia are stained green with an antibody against acetylated tubulin). (Bottom) PCP defects are scored based on the misorientation of these sterociliary bundles on inner (IHC) and outer (OHC) hair cells in whole-mount preparations of the organ of Corti. (B, top) In a textbook example of PCP, the surface of the fly wing is covered with a neatly organized array of hairs, all of which point toward the distal side. (Bottom) Defects in PCP are typically scored based on the misorientation of wing hairs. (C) Molecular control of PCP in the Drosophila wing. Complexes of the transmembrane proteins flamingo and vang, together with the cytoplasmic protein prickle, accumulate at the proximal end of the cell. At the distal border, flamingo and frizzled accumulate together with dishevelled and diego. Interactions between the extracellular domains of flamingo, frizzled, and vang are thought to play an important role in maintaining these complexes at opposite sides of the cell boundary (Chen et al. 2008; Wu and Mlodzik 2008). In addition, diego has been proposed to promote fz/dsh signaling, whereas vang/pk is thought to prevent recruitment of dsh to the cell membrane, something that is a prerequisite for PCP signaling (Tree et al. 2002; Das et al. 2004; Jenny et al. 2005).

Figure 2.

Knowledge gaps. In the absence of robust and quantitative readouts, it has remained difficult to dissect the biological processes (left) in which alternative Wnt-signaling components (center) play a role in distinct signal transduction events (right). For instance, despite the fact that multiple Wnt-pathway components show a genetic interaction with core PCP/CE proteins (boxed in the center), it remains unknown how Wnts and their (co-)receptors are tied to the core PCP/CE machinery at the biochemical level. As an example, the core PCP/CE protein vang/Vangl2 plays a central role in tissue morphogenesis. Animals deficient for vang/Vangl2 display severe defects in PCP (red ellipse; e.g., cochlear hair cell orientation) and CE (yellow ellipse; e.g., neural tube closure), as well as in developmental processes that have not (yet) been definitively linked to either PCP or CE (blue ellipse; e.g., lung branching morphogenesis). A genetic interaction with Vangl2 has been shown for both Wnt5a and Ror2, and Wnt5a/Ror2 has been reported to phosphorylate Vangl2 in the murine limb bud (Qian et al. 2007; Yamamoto et al. 2008; Gao et al. 2011). The most robust assay to monitor Wnt5a/Ror2 signaling in vitro is inhibition of the Wnt/β-catenin-responsive TOPFLASH luciferase reporter (green ellipse). However, Wnt5a and Ror2 have also been reported to activate JNK and AP-1 in mammalian cell culture experiments (orange ellipse). It is unknown how far these two responses overlap and whether they involve Vangl2. Conversely, it is unknown whether either Wnt5a or Ror2 plays a direct role in the diverse tissue-morphogenetic events in which Vangl2 has been implicated.