Wnt-Frizzled/planar cell polarity signaling: cellular orientation by facing the wind (Wnt)

Abstract

The establishment of planar cell polarity (PCP) in epithelial and mesenchymal cells is a critical, evolutionarily conserved process during development and organogenesis. Analyses in Drosophila and several vertebrate model organisms have contributed a wealth of information on the regulation of PCP. A key conserved pathway regulating PCP, the so-called core Wnt-Frizzled PCP (Fz/PCP) signaling pathway, was initially identified through genetic studies of Drosophila. PCP studies in vertebrates, most notably mouse and zebrafish, have identified novel factors in PCP signaling and have also defined cellular features requiring PCP signaling input. These studies have shifted focus to the role of Van Gogh (Vang)/Vangl genes in this molecular system. This review focuses on new insights into the core Fz/Vangl/PCP pathway and recent advances in Drosophila and vertebrate PCP studies. We attempt to integrate these within the existing core Fz/Vangl/PCP signaling framework.

Keywords: Dishevelled; Frizzled; PCP; Vangl; Wnt; morphogenesis.

Figure 1

Schematic depiction of Wnt-Frizzled/planar cell polarity (Fz/PCP) core component interactions across a two-cell border in Drosophila. Fz and Van Gogh (Vang) act in the interpretation of both long-range signal(s)—likely Wg/dWnt4 gradients—and short-range/local cell-cell transmembrane interactions. The latter is also mediated by the homophilic interactions of Flamingo (Fmi) and Furrowed (Fw), which are thought to physically interact with Fz and Vang and just Fz, respectively. The cytoplasmic components Dishevelled (Dsh), Diego (Dgo), and Prickle (Pk) are essential for negative intracellular feedback loops within individual cells, as they antagonize each other, and for activating intracellular pathways; for example, Dsh promotes actin polymerization by activating/localizing Rho-family GTPases and downstream effectors such as dROK (Rho-associated kinase). Inturned (In) and Fuzzy (Fy) serve to recruit Multiple wing hairs (Mwh), which is thought to inhibit actin polymerization. For more details and for Fz-Dsh downstream intracellular signaling pathways, readers are referred to Adler (2002), Mlodzik (2002), Strutt (2003), and Veeman et al. (2003).

Figure 2

Schematic presentation of Frizzled/planar cell polarity (Fz/PCP) core component interactions across an epithelial layer (apical view) relative to a Wnt (Wg/dWnt4) concentration gradient. An initial asymmetry along the Wg/Wnt4 gradient is subsequently amplified via negative intracellular and positive intercellular interactions among the core PCP factors. At least in the eye and wing of Drosophila, the PCP orientation axis is along a Wnt concentration slope. It is likely that in other tissues in which PCP alignment is more complicated relative to Wnt gradients, such as the Drosophila leg, a more complex morphogen alignment is in place. Abbreviations: Dgo, Diego; Dsh, Dishevelled; Fmi, Flamingo; Pk, Prickle; Vang, Van Gogh.

Figure 3

Conserved asymmetrical localization patterns of core PCP components in six distinct epithelial and mesenchymal tissues (a–f ) in developing vertebrate embryos. In response to global cues (likely provided by Wnts), PCP is established. Molecularly, PCP establishment leads to coordinated, asymmetrical localization of core PCP components uniformly across all cells in any given tissue. It is interesting that the pattern of asymmetrical localization is conserved among different tissues. Moreover, the spatial relationships between global cue direction and the resulting asymmetrical pattern of polarity protein localization are also conserved. Abbreviations: A, anterior; CE, convergent extension; Di, distal; Dvl, Dishevelled; FzD, Frizzled; HC, hair cell; L, lateral; M, medial; P, posterior; PCP, planar cell polarity; Pk, Prickle; Pr, proximal; SC, supporting cell; Vangl, Van Gogh–like.

Figure 4

The Wnt5a gradient controls directional limb elongation by regulating planar cell polarity (PCP). The Wnt5a signal induces Ror2-Vangl2 (Van Gogh–like 2) complex formation; it is likely that a Frizzled family member also serves a key function as a Wnt coreceptor in this complex. As a result, Vangl2 is phosphorylated at conserved Ser and Thr residues in a Wnt5a dose-dependent manner. Therefore, a Wnt5a gradient is translated into a Vangl2 phosphorylation gradient. As Vangl2 activity appears to be regulated by phosphorylation (Gao et al. 2011), the Wnt5a gradient is translated into a Vangl2 activity gradient in the limb. A chondrocyte in the middle of the newly formed cartilage can sense its positional information by comparing Vangl2 activity with that of its immediate neighbors through cell-cell interactions. Such cell-cell interactions eventually lead to asymmetrical Vangl2 protein localization through feedback loops, laying the groundwork for further asymmetric cellular behavior, such as directional cartilage elongation.