From instruction to output: Wnt/PCP signaling in development and cancer

Abstract

Planar cell polarity (PCP) provides positional information to direct tissue patterning and morphogenesis. While much of the molecular detail of the pathway has been delineated in Drosophila, ensuing studies have shown considerable conservation of both the components and mechanisms of signaling in vertebrates. A recognized feature of PCP is the asymmetric localization of components that translates a global directional cue into a polarized downstream output. Here we discuss recent advances in the PCP field, from the organization of these asymmetric complexes to their upstream directional regulation by Wnt ligands. We also discuss the impact of Wnt/PCP signaling in disease and more specifically an emerging role in cancer progression.

Figure 1

Core PCP protein complex localization. (A) A classical view of the asymmetric localization of PCP proteins. Fmi, a non-typical cadherin localizes to both sides of the cell and forms an intracellular bridge; the two transmembrane proteins Fz and Vang interact with Fmi and in turn recruit the cytoplasmic proteins; Dsh, Dgo and Pk. Positive and negative feedback mechanisms act to enhance asymmetric localization [–5,8,10]. (B) An updated model of the stoichiometry of PCP complexes at the junction in wild-type pupal wings (Strutt). In this model, the respective ratio of complex members is 2Fmi:1Fz:2Dsh:1Dgo:6Vang:1Pk. Experiments to vary gene dosage revealed this stoichiometry could be altered without a significant affect to asymmetric protein localization putting the idea forward for a signalosome-like organization [13]. This was with the exception of Fz and Vang, whose levels must be maintained relative to their binding partners [13], to promote feedback interactions and support asymmetric localization.

Figure 2

Wnt gradients align with PCP complex localization. (A) Schematic of a Drosophila wing, which exhibits a low proximal to high distal Wg and dWnt4 gradient. Core PCP proteins align to this gradient with the Fz complex localizing at the distal side of the cell, which receives higher levels of Wnt ligand [29]. (B) Schematic of developing Drosophila eye. The ommatidial preclusters of the eye show distinct localization of PCP complex members in photoreceptors 3 and 4. In this tissue, the localization is more complex due to input from additional developmental signaling pathways. PCP localization is, however, still in alignment with the Wnt gradient, which is lowest at the equator and strongest at each pole. On either side of the equator, Fz is seen localized to the Wnt-facing side of the R3 cell [45]. (C) Schematic of the mouse node, which displays opposing gradients of Wnt5a/b and the Wnt inhibitors Sfrp1/2/5. There is additionally a flat gradient of Wnt11, whose activity could potentially be modulated by the Sfrps. The low Wnt activity here correlates with localization of Vangl complexes, leading to appropriate positioning of the basal body and cilia [31]. This study also reveals a conserved role for asymmetric PCP localization in basal body positioning, previously demonstrated in Drosophila wings [46]. (D) Schematic of the developing mouse limb. A gradient of Wnt5a was shown to correlate with the asymmetric localization of phosphorylated Vangl2, however, whether Wnt5a is instructive in this case remains to be determined [36].

Figure 3

Asymmetric PCP localization is a feature in development and disease. (A) Schematic of convergent extension in vertebrate development. The tissue becomes elongated in the anterior to posterior axis through intercalating movements in the medial-lateral axis. Cells show asymmetric localization of PCP components with the Vangl complex localizing at the anterior cell border [47,48]. (B) Schematic of a migrating breast cancer cell. Asymmetry of core PCP components can be seen within a single cell as opposed to a tissue, with the Fz complex localizing at protrusions and the Vangl complex localizing laterally [42]. The feedback interactions between the complex members enable the formation of distinct domains within the cell to regulate localized actin dynamics [43]. While both processes are examples of cell migration, the role of PCP differs. During convergent extension, PCP provides directional input to enable remodeling of specific junctions and cell intercalation, while during cancer cell migration, PCP derives no directional value and instead facilitates confined cytoskeletal remodeling. Despite this, in each case the spatial regulation of downstream signaling and correlation with asymmetric protein localization is a constant.