Wg and Wnt4 provide long-range directional input to planar cell polarity orientation in Drosophila

Abstract

Planar cell polarity (PCP) is cellular polarity within the plane of an epithelial tissue or organ. PCP is established through interactions of the core Frizzled(Fz)/PCP factors and although their molecular interactions are beginning to be understood, the upstream input providing directional bias/polarity axis remains unknown. Among core PCP genes, Fz is unique as it regulates PCP both cell-autonomously and non-autonomously, with the extra-cellular domain of Fz acting as a ligand for Van-Gogh (Vang). We demonstrate in Drosophila wings that Wg and dWnt4 provide instructive regulatory input for PCP axis determination, establishing polarity axes along their graded distribution and perpendicular to their expression domain borders. Loss-of-function studies reveal that Wg/dWnt4 act redundantly in PCP determination. They affect PCP by modulating the intercellular interaction between Fz and Vang, which is thought to be a key step in setting up initial polarity, thus providing directionality to the PCP process.

Planar Cell Polarity Pathway in Kidney Development and Function

“…However, this upstream-downstream relationship between the global and core PCP modules has been questioned and alternative model has been proposed in which the two cassettes function in parallel with some cross talk between them [58,59]. Recently, Wu et al showed that an early instructive PCP signal is provided by the two Drosophila Wnt members, Wingless (Wg) and Wnt4, which are expressed in a gradient and act redundantly as Fz ligands [48]. Wg/Wnt4 -Fz binding regulates Fz activity, which, in turn, provides the planar directional cue and triggers asymmetric relocalization of PCP protein complexes.…”

“…The asymmetry is sustained by inter-and intracellular mechanisms that collectively generate a negative feedback loop that enhances and sustains asymmetric PCP protein distribution [61,65,66]. Wu et al showed that Fz (which is localized at the distal part of one cell) binds to an extracellular loop of Vang localized at the proximal side of a neighboring cell; stability of the Fz-Vang intercellular interaction depends on Wg/Wnt4 concentration [48]. The Fz-Vang extracellular binding leads to stabilization of both Vang/Pk and Fz/Dvl complexes to the opposite cellular domains [66].…”

“…The second class of PCP molecules are encoded by "core" PCP genes: the WNT receptor Frizzled (Fz), transmembrane proteins Van Gogh/Strabismus (Vang/Stbm), and Flamingo/Starry Night (Fmi/Stan) and cytoplasmic proteins Dishevelled (Dsh/Dvl), Prickle (Pk), and Diego (Dg) [46,47] (Figure 1). Core PCP proteins define the axis of planar polarization in each cell and are sensitive to long-range input from upstream polarity cues [48]. Mutations of the core genes result in PCP defects in all fruit fly tissues studied [10].…”

Planar cell polarity in moving cells: think globally, act locally

“…It should also be noted that the core PCP pathway is often referred to as the non-canonical Wnt/PCP pathway, because it involves Fz receptors and Dvl homologs in a β-catenin-independent signaling pathway. Although the role of Wnts in Drosophila planar polarity is debated (Chen et al, 2008;Wu et al, 2013), Wnt ligands are essential as permissive cues for many vertebrate PCP processes including some PCP-dependent cell movements (Heisenberg et al, 2000;Qian et al, 2007), although recent work has identified an instructive role in the establishment of planar polarity in the ectoderm (Chu and Sokol, 2016).…”

Dynamic intracellular distribution of Vangl2 during cell polarization in zebrafish gastrula

“…A tight regulation of the composition of these complexes on opposite cell membranes, and consequently on adjacent membranes of two neighboring cells, is essential for the polarizing signal to be propagated across several cell diameters (Adler et al, 2000). Recent studies also implicate Wg and Wnt4 in providing long-range directional input in the Drosophila wing (Wu et al, 2013). Zebrafish embryos carrying mutations in several of the Wnt/PCP pathway core components and in Wnt11/ Wnt5 ligands exhibit a characteristic morphogenetic phenotype, with shorter AP and broader ML body axes due to impaired C&E movements (Heisenberg et al, 2000;Kilian et al, 2003;Marlow et al, 1998).…”