Planar cell polarity (PCP) reflects cellular orientation within the plane of an epithelium. PCP is crucial during many biological patterning processes and for organ function. It is omnipresent, from ...convergent-extension mechanisms during early development through to terminal organogenesis, and it regulates many aspects of cell positioning and orientation during tissue morphogenesis, organ development and homeostasis. Suzanne Eaton used the power of
as a model system to study PCP, but her vision of, and impact on, PCP studies in flies translates to all animal models. As I highlight here, Suzanne's incorporation of quantitative biophysical studies of whole tissues, integrated with the detailed cell biology of PCP phenomena, completely changed how the field studies this intriguing feature. Moreover, Suzanne's impact on ongoing and future PCP studies is fundamental, long-lasting and transformative.
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.
•PCP complexes are robust to changes in protein levels.•Complexes may exist in a signalosome-like assembly at cell junctions.•Wnt ligands play a conserved instructive function in PCP ...signaling.•Vang(l) phosphorylation is required for efficient asymmetric localization.•Wnt/PCP has an underappreciated role in cancer progression.
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.
Most, if not all, cell types and tissues display several aspects of polarization. In addition to the ubiquitous epithelial cell polarity along the apical-basolateral axis, many epithelial tissues and ...organs are also polarized within the plane of the epithelium. This is generally referred to as planar cell polarity (PCP; or historically, tissue polarity). Genetic screens in Drosophila pioneered the discovery of core PCP factors, and subsequent work in vertebrates has established that the respective pathways are evolutionarily conserved. PCP is not restricted only to epithelial tissues but is also found in mesenchymal cells, where it can regulate cell migration and cell intercalation. Moreover, particularly in vertebrates, the conserved core PCP signaling factors have recently been found to be associated with the orientation or formation of cilia. This review discusses new developments in the molecular understanding of PCP establishment in Drosophila and vertebrates; these developments are integrated with new evidence that links PCP signaling to human disease.
In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription ...regulator 1 (
) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the
ortholog
resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of
led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. Because
disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for
involvement in a variety of inherited and acquired human disorders.
Many types of cell show different aspects of polarization. Epithelial cells display a ubiquitous apical–basolateral polarity but often are also polarized in the plane of the epithelium – a feature ...referred to as ‘planar cell polarity’ (PCP). In
Drosophila all adult epithelial cuticular structures are polarized within the plane, whereas in vertebrates examples of PCP include aspects of skin development, features of the inner ear epithelium, and the morphology and behavior of mesenchymal cells undergoing the morphogenetic movement called ‘convergent extension’. Recent advances in the study of PCP establishment are beginning to unravel the molecular mechanisms that underlie this aspect of cell and tissue differentiation. Here I discuss new developments in our molecular understanding of PCP in
Drosophila and compare them towhat is known about the regulation of convergent extension in vertebrates.
The ‘other side’ of Wnt/Frizzled signaling is revealed as a conserved signaling mechanism regulating planar cell polarization in different contexts.
The phenomenon of tissue fluidity-cells' ability to rearrange relative to each other in confluent tissues-has been linked to several morphogenetic processes and diseases, yet few molecular regulators ...of tissue fluidity are known. Ommatidial rotation (OR), directed by planar cell polarity signaling, occurs during Drosophila eye morphogenesis and shares many features with polarized cellular migration in vertebrates. We utilize in vivo live imaging analysis tools to quantify dynamic cellular morphologies during OR, revealing that OR is driven autonomously by ommatidial cell clusters rotating in successive pulses within a permissive substrate. Through analysis of a rotation-specific nemo mutant, we demonstrate that precise regulation of junctional E-cadherin levels is critical for modulating the mechanical properties of the tissue to allow rotation to progress. Our study defines Nemo as a molecular tool to induce a transition from solid-like tissues to more viscoelastic tissues broadening our molecular understanding of tissue fluidity.
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.
Wnt/Wingless (Wg) signaling is critical in development and disease, including cancer. Canonical Wnt signaling is mediated by β-catenin/Armadillo (Arm in Drosophila) transducing signals to the ...nucleus, with IFT-A/Kinesin 2 complexes promoting nuclear translocation of β-catenin/Arm. Here, we demonstrate that a conserved small N-terminal Arm34–87/β-catenin peptide binds to IFT140, acting as a dominant interference tool to attenuate Wg/Wnt signaling in vivo. Arm34–87 expression antagonizes endogenous Wnt/Wg signaling, resulting in the reduction of its target expression. Arm34–87 inhibits Wg/Wnt signaling by interfering with nuclear translocation of endogenous Arm/β-catenin, and this can be modulated by levels of wild-type β-catenin or IFT140, with the Arm34–87 effect being enhanced or suppressed. Importantly, this mechanism is conserved in mammals with the equivalent β-catenin24–79 peptide blocking nuclear translocation and pathway activation, including in cancer cells. Our work indicates that Wnt signaling can be regulated by a defined N-terminal β-catenin peptide and thus might serve as an entry point for therapeutic applications to attenuate Wnt/β-catenin signaling.
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•N-terminal β-catenin fragment acts as a dominant interference tool to inhibit Wnt signaling•It inhibits Wnt signaling by interfering with nuclear translocation of endogenous β-catenin•It serves as entry point for therapeutic applications to attenuate Wnt signaling
Vuong and Mlodzik demonstrate that an N-terminal peptide of β-catenin inhibits nuclear translocation of endogenous full-length β-catenin. The inhibitory effect of the peptide is at the level of stable β-catenin, and hence, it can attenuate Wnt signaling in mutant contexts that lead to stable β-catenin or can even stabilize mutations within β-catenin.
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