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PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates

Abstract

In addition to the apical–basal polarity pathway operating in epithelial cells, a planar cell polarity (PCP) pathway establishes polarity within the plane of epithelial tissues and is conserved from Drosophila to mammals. In Drosophila, a ‘core’ group of PCP genes including frizzled (fz), flamingo/starry night, dishevelled (dsh), Van Gogh/strabismus and prickle, function to regulate wing hair, bristle and ommatidial polarity1,2,3. In vertebrates, the PCP pathway regulates convergent extension movements and neural tube closure3,4,5, as well as the orientation of stereociliary bundles of sensory hair cells in the inner ear6. Here we show that a mutation in the mouse protein tyrosine kinase 7 (PTK7) gene, which encodes an evolutionarily conserved transmembrane protein with tyrosine kinase homology, disrupts neural tube closure and stereociliary bundle orientation, and shows genetic interactions with a mutation in the mouse Van Gogh homologue vangl2. We also show that PTK7 is dynamically localized during hair cell polarization, and that the Xenopus homologue of PTK7 is required for neural convergent extension and neural tube closure. These results identify PTK7 as a novel regulator of PCP in vertebrates.

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Figure 1: PTK7 loss-of-function phenotypes.
Figure 2: PCP phenotype in PTK7 mutant cochleae.
Figure 3: The PTK7 mutation genetically interacts with the Lp mutation.
Figure 4: PTK7 regulates convergent extension and neural tube closure in Xenopus.

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Acknowledgements

We thank J. Perrino and J. Mulholland at the Stanford Cell Sciences Imaging Facility for assistance with scanning electron microscopy analysis; J. Zhong for technical support; R. M. Harland, J. E. Johnson, T. M. Jessell and M. P. Scott for reagents; D. Brown for helpful discussions; and C. I. Bargmann, S. K. McConnell, J. D. Axelrod, M. A. Simon, T. Venkatesh, U. Grieshammer, L. V. Goodrich and members of the Tessier-Lavigne laboratory for helpful comments on the manuscript. Funding for this project was provided by grants to M.T.L. from the NIMH, and to J.C.B. from the NIH. X.L. was supported by a fellowship from the Damon Runyon Cancer Research Foundation, and A.G.M.B. by the Stanford University Dean's Fellowship. M.T.L. was an investigator of the Howard Hughes Medical Institute.

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Correspondence to Marc Tessier-Lavigne.

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Supplementary information

Supplementary Figure S1

PTK7:βgeo expression during gastrulation and neurulation. (JPG 52 kb)

Supplementary Figure S2

Dorsal-ventral patterning of the spinal cord is normal in PTK7 mutants. (JPG 63 kb)

Supplementary Figure S3

PTK7 mutants exhibit other developmental abnormalities. (JPG 21 kb)

Supplementary Figure Legends (DOC 22 kb)

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Lu, X., Borchers, A., Jolicoeur, C. et al. PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature 430, 93–98 (2004). https://doi.org/10.1038/nature02677

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