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Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility

Key Points

  • Frizzled (Fz)/planar cell polarity (PCP) signalling is a conserved mechanism regulating the polarity of cells along the axes of a tissue.

  • Fz/PCP regulates a diverse array of processes including the orientation of cellular hairs and the ommatidia of the compound eye in Drosophila melanogaster, and convergent extension, inner ear development and hair formation in vertebrates.

  • Genetic analysis in D. melanogaster has identified a group of core components, Frizzled (FZ), Strabismus (STBM), Flamingo (FMI), Dishevelled (DSH), Prickle (PK) and Diego (DGO), which are essential for proper PCP signalling, leading to DSH mediated downstream effects/tissue-specific responses.

  • Genetic and biochemical evidence indicate the existence of two antagonistic complexes, FZ–DSH–DGO and STBM–PK, which are localized asymmetrically in cells. However, the localization of these factors in vertebrate systems still needs to be determined.

  • Fz/PCP signalling regulates cell motility in the contexts of convergent extension and ommatidial rotation, in which these polarizing signals might regulate cell adhesive contacts through the recycling of E-cadherin.

  • The mechanisms regulating global coordination of Fz/PCP in tissues is still being determined. Vertebrate PCP involves Wnt family members, but it is not known whether this is instructive or permissive, whereas evidence from D. melanogaster indicates Fat, Dachsous and Four-jointed as possible upstream regulators.

Abstract

Signalling through Frizzled (Fz)/planar cell polarity (PCP) is a conserved mechanism that polarizes cells along specific axes in a tissue. Genetic screens in Drosophila melanogaster pioneered the discovery of core PCP factors, which regulate the orientation of hairs on wings and facets in eyes. Recent genetic evidence shows that the Fz/PCP pathway is conserved in vertebrates and is crucial for disparate processes as gastrulation and sensory cell orientation. Fz/PCP signalling depends on complex interactions between core components, leading to their asymmetric distribution and ultimately polarized activity in a cell. Whereas several mechanistic aspects of PCP have been uncovered, the global coordination of this polarization remains debated.

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Figure 1: PCP and the organization of several tissues in a variety of systems.
Figure 2: Subcellular distribution of core Fz/PCP factors in Drosophila melanogaster and vertebrates.
Figure 3: The Fz/PCP pathway regulates cell motility during convergent extension and ommatidial rotation.
Figure 4: Activity slopes of Fz/PCP signalling and the FT–DS–FJ interactions in different Drosophila melanogaster tissues.

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Acknowledgements

We are grateful to D. del Alamo, W. Gault and S. Sokol for comments on the manuscript, to A. Jenny for help with Fig. 2, and to all members of the Mlodzik's laboratory for discussions. We thank B. Ciruna, M.W. Kelley and J. Nathans for some of the panels shown in Fig. 1 and discussions. We apologize to investigators whose work is only cited indirectly through earlier reviews. Our work is supported by grants from the National Institute of General Medical Sciences and the National Eye Institute of the National Institutes of Health.

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DATABASES

ZFIN

Kny

Rok2

tri

Wnt5b

Wnt11

Glossary

Epithelium

A tissue in which the cells are arranged in sheets or tubes and have strict apical–basal polarity and strong connections to one another through various cell–cell junctions and contacts.

Compound eye

Insect eyes are composed of several hundreds of light-sensitive units called ommatidia or facets, each having its own refractive system. Each ommatidium provides a single input leading to the formation of an entire image.

Mesenchymal cells

Cells that do not have apical basal polarity and make minimal contacts with one another but can migrate to distant sites.

Convergent extension

A process that is extensively studied during vertebrate gastrulation and involves a variety of cell behaviours, which ultimately lead to a tissue narrowing along one axis and its lengthening along a perpendicular axis.

Ciliogenesis

The assembly of a cilium, which is a specialized organelle composed of a characteristic panel of longitudinally oriented microtubules.

Cell protrusions

Projections of the plasma membrane that involve dynamic actin assembly. Examples include lamellipodia, filopodia and pseudopodia.

Apical cortex

This is the region of a cell that includes and is immediately adjacent to the apical plasma membrane.

SOP cells

Sensory organ precursor (SOP) cells are ectodermal cells that will give rise to a sensory bristle in the adult Drosophila melanogaster epidermis through a series of asymmetric cell divisions.

Gastrulation

The process during animal embryogenesis in which the three germ layers, endoderm, mesoderm and ectoderm are separated through a series of dramatic cell movements.

Neurulation

The vertebrate process by which the neural plate and subsequently the neural tube are formed.

Stereocilia

A specialized microvillus that projects from the surface of the inner ear sensory cells and is composed of a bundle of actin filaments rather than microtubules, and is therefore not a true cilium.

PAR proteins

Proteins that are involved in the establishment of cell polarity and were identified in Caenorhabditis elegans as partitioning defective (par) mutants, which have defects in asymmetric cell division in the early embryo.

ArfGAP

A GTPase activating protein (GAP) that accelerates the rate of GTP hydrolysis regulating the activation state of the ADP-ribosylation factor (Arf) family of small GTPases.

E-cadherin

An epithelial specific member of the cadherin family that mediates Ca2+ dependent cell adhesion and is the primary cadherin in adherens junctions.

Adherens junction

A cell–cell adhesion complex mediated by homophilic cadherin interactions extracellularly and cadherin–catenin complexes linked to the actin cytoskeleton intracellularly. Adherens junctions form an apical belt around epithelial cells known as zonula adherens.

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Seifert, J., Mlodzik, M. Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility. Nat Rev Genet 8, 126–138 (2007). https://doi.org/10.1038/nrg2042

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