A quest for the mechanism regulating global planar cell polarity of tissues

Abstract

Most epithelial cells, besides their ubiquitous apical-basal polarity, are polarized within the plane of the epithelium, which is called planar cell polarity (PCP). Using Drosophila as a model, meaningful progress has been made in the identification of key PCP factors and the dissection of their intracellular molecular interactions. The long-range, global aspects of coordinated polarization and the overlying regulatory mechanisms that create the initial polarity direction have, however, remained elusive. Several recent publications have outlined potential mechanisms of how the global regulation of PCP might be controlled and how the distinct core factor groups might interact via frizzled, Van Gogh or flamingo. This review focuses on these exciting features and attempts to provide an integrated picture of these recent and novel insights.

Figure I

Apical localization of junctional protein complexes and PCP components.

Figure I

The relationship of Ds, Fj gradients and proposed Ft and Fz activity gradients in the eye and wing. (a) In the eye, Ds is expressed in a gradient that is highest at the poles, and low at the equator. Fj expression is highest at the equator and low at the poles. Thus, the Fz activity slope and Fj gradient are opposite to the Ds gradient. (b) In the wing, Ds is high proximally and low at the distal end and Fj is again the opposite. In contrast to the eye, however, the Fz activity slope is the same as Ds and opposite to Fj. Fz is expressed evenly in both eye and wing; a Fz activity gradient is inferred from genetic data. In summary, the slope of the Fz ‘activity’ gradient and Ds–Fj expression gradients (regulating Ft ‘activity’) have the relative opposite directions in the two tissues, suggesting that interactions between Fz–Fm-group and Ft–Ds-group factors, if any, must be more complicated than a simple one way regulatory input.

Figure 1

Asymmetric localization of core PCP molecules using the fly wing as an example. (a) Top view of wing cells. At early pupal stages (left), the core PCP molecules are evenly distributed as a ring at and/or just apical to the adherens junctions (not illustrated). At later pupal stages (right), a Fz–Dsh–Dgo–Fmi complex is concentrated at distal edges of cells and the Vang–Pk–Fmi complex is concentrated at proximal edges of cells. (b) Schematic presentation of the Fz–Fmi-group PCP factors and their interactions. Fz is shown in orange with its interacting partners Dsh (yellow, with its specific domains DIX, PDZ and DEP [from left to right] in light red) and Dgo (red with its Ankyrin repeat domains in light blue). Fmi is shown in green. Vang is shown in light blue and its interacting partner Pk in dark blue (the PET and 3 LIM domains are indicated by lighter shades of blue). Fz can bind to Vang primarily via its CRD and Fmi displays homophilic interactions. Dsh and Dgo physically interact and can antagonize Pk (red lines on left); Pk antagonizes Dsh (red lines on right). The downstream effectors of non-autonomous signaling are unknown (black arrows with question marks).

Figure 2

Schematic illustrations displaying non-autonomous effects of clones of different genetic backgrounds in Drosophila wings. Orientation of cells surrounding mutant clones is indicated by arrows (black arrows for normal orientation and orange arrows for repolarized orientation). The mutant cells themselves (marked by red fields) show random orientation, which is not indicated by additional means. (a) Wild-type (wt) clone does not change polarity (for comparison). (b) dsh⁻ mutant clone causes polarity defects within mutant cells but does not affect the polarity of neighboring cells (black arrows). (c) fz⁻ mutant clone causes wild-type distal neighboring cells to reverse polarity and point toward the clone (orange arrows). (d) Vang⁻ mutant clone causes proximal wild-type neighboring cells to reverse polarity and point away from mutant tissue (orange arrows). (e) Fz overexpressing clone (fz²⁺) causes neighboring cells to point away from clone (orange arrows). (f) fz⁻, Vang⁻ double mutant clone causes neighboring wild-type cells to point towards mutant tissue (orange arrows; very similar to fz⁻ mutant clones). (g) fmi⁻ mutant clone has polarity defects inside mutant tissue but does not affect polarity of wild-type neighboring cells. (h) fmi overexpressing clone (fmi²⁺) causes wild-type neighboring cells to point toward the clone (orange arrows; similar to fz⁻ mutant patches). See main text for discussion.

Figure 3

Illustration of non-autonomous PCP signaling models. Top view of pupal wing cells. (a) Homophilic Fmi–Fmi intercellular bridge mediates the intercellular interaction between Fz and Vang [39]. This model proposes that Fz activates itself in the neighboring cell through an Fmi–Fmi intercellular bridge. Fz inhibits Fmi in the same cell and Fmi activates Vang in the neighboring cell. Vang antagonizes Fz activity. This regulation leads to the formation of a feedback loop. The interaction trails (following either black or grey signs in the panel) indicate that Fz activates Fz in neighboring cells. This would lead to an overall increase in Fz activity in the whole field. A gradient of ‘factor X’ is proposed to inhibit Fz activity. As a result, a Fz activity gradient is generated in response to this X-gradient. The model is based on data presented in Refs [39,50]. (b) A direct ‘Fz–Vang’ interaction model: (i) A wt cell in the middle ‘senses’ less Fz in a fz⁻ mutant cell on right as compared to wt cell on left through the Fz–Vang interaction. Both Vang and Fz form complexes with Fmi. The Fmi–Fmi interaction brings Fz and Vang close to each other and stabilizes them at apical junctional regions, thus facilitating their interaction. (ii) A wt cell in the middle senses more Fz in the Fz overexpressing cell on the right as compared to wt cell on left. Polarity direction is adjusted accordingly. (iii) Fmi is overexpressed in right cell. Due to the large amount of Fmi in the apical junctional region, it outcompetes Fz–Fmi complexes to interact with Vang–Fmi and thus relatively less Fz is able to bind to Vang in the middle cell. As a consequence, Vang ‘detects’ less Fz in the Fmi-overexpressing cell as compared to wt cells (and polarity is changed accordingly), although absolute levels of Fz are not decreased in Fmi-overexpressing cells.

Figure 4

Summary of the relationships between the PCP signaling events. The diagram schematizes the relationships among the non-autonomous and autonomous Fz–Fmi core PCP signaling and Ft/Ds PCP signaling. The two core groups seem to act in parallel. The nature of Factor X to provide a polarization bias for the Fz–Fmi group (a Wnt or other) remains unknown.