planar cell polarity

In multicellular organisms, cells are polarized in the plane of the epithelial sheet, revealed in some cell types by oriented hairs or cilia. Many of the underlying genes have been identified in Drosophila melanogaster and are conserved in vertebrates.

The evolutionarily conserved planar cell polarity (PCP) pathway (or noncanonical Wnt pathway) drives several important cellular processes, including epithelial cell polarization, cell migration and mitotic spindle orientation.

In vertebrates, PCP genes have a vital role in polarized convergent extension movements during gastrulation and neurulation.

PCP pathway

PCP signaling involves a noncanonical Wnt/frizzled (WNTs/FZDs) pathway where Wnt (WNTs) binds to the Fz receptor (FZDs) leading to recruitment and activation of Dishevelled (Dsh in Drosophila and Dvl in vertebrates) (DVLs). The identity of the substrate binding to Fz (FZDs) as being Wnt (WNTs) is still not confirmed.

PCP activation requires formation of a multiprotein complex including two transmembrane proteins, Vangl (Stbm/Vang in Drosophila and Vangl in vertebrates) and Fmi/Stan/Celsr (Flamingo or Starry night in Drosophila and Celsr in vertebrates), and three cytoplasmic proteins, Dsh/Dvl, Diego (Dgo, related to Inversin in vertebrates) and Prickle (Pk).

These proteins acquire an asymmetric localization at the plasma membrane that is crucial for proper PCP signaling.

Scribble (Scrb) is a cytoplasmic protein involved in apical-basal polarity in the fly that binds to and genetically interacts with Vangl, suggesting a role in PCP signaling.

Protein tyrosine kinase 7 (PTK7) is a conserved transmembrane protein that genetically interacts with Vangl2 in vertebrates.

Downstream effectors of PCP signaling include small Rho GTPases (Rho/Rac/Daam) and the c-Jun N-terminal kinase (JNK) that act on the cytoskeleton and induce cellular polarizing events.

Two transmembrane proteins, Inturned (In) and Fuzzy (Fy), act as downstream effectors of PCP signaling. In and Fy are also required for ciliogenesis where defects affect Hedgehog (HH) signaling through Gli transcription factors. In and Dvl are colocalized near the basal apparatus of cilia. These components suggest a link between PCP, ciliogenesis and SHH signaling pathway.

Pathology

 Mice with mutations in genes involved in Bardet-Biedl syndrome (BBS), a disorder associated with ciliary dysfunction, share phenotypes with PCP mutants including open eyelids, neural tube defects and disrupted cochlear stereociliary bundles.

• There are genetic interactions between BBS genes and a PCP gene in both mouse (Ltap, also called Vangl2) and zebrafish (vangl2).
• In zebrafish, the augmented phenotype results from enhanced defective convergent extension movements. Vangl2 localizes to the basal body and axoneme of ciliated cells, a pattern reminiscent of that of the BBS proteins.
• Cilia are intrinsically involved in PCP processes.

See also

 cellualr polarity

References

 Lawrence PA, Struhl G, Casal J. Planar cell polarity: one or two pathways? Nat Rev Genet. 2007 Jul;8(7):555-63. PMID: 17563758

 Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP, Munro PM, Fisher S, Tan PL, Phillips HM, Leroux MR, Henderson DJ, Murdoch JN, Copp AJ, Eliot MM, Lupski JR, Kemp DT, Dollfus H, Tada M, Katsanis N, Forge A, Beales PL. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet. 2005 Oct;37(10):1135-40. PMID: 16170314