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Regulation of polarized extension and planar cell polarity in the cochlea by the vertebrate PCP pathway

Abstract

The mammalian auditory sensory organ, the organ of Corti, consists of sensory hair cells with uniformly oriented stereocilia on the apical surfaces and has a distinct planar cell polarity (PCP) parallel to the sensory epithelium1,2,3. It is not certain how this polarity is achieved during differentiation4,5. Here we show that the organ of Corti is formed from a thicker and shorter postmitotic primordium through unidirectional extension, characteristic of cellular intercalation known as convergent extension6. Mutations in the PCP pathway interfere with this extension, resulting a shorter and wider cochlea as well as misorientation of stereocilia. Furthermore, parallel to the homologous pathway in Drosophila melanogaster7,8, a mammalian PCP component Dishevelled2 shows PCP-dependent polarized subcellular localization across the organ of Corti. Taken together, these data suggest that there is a conserved molecular mechanism for PCP pathways in invertebrates and vertebrates and indicate that the mammalian PCP pathway might directly couple cellular intercalations to PCP establishment in the cochlea.

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Figure 1: Differentiation of the organ of Corti from its postmitotic precursor domain.
Figure 2: Unidirectional extension of the organ of Corti in vitro.
Figure 3: Presence of a functional PCP pathway in the developing organ of Corti.
Figure 4: The stereocilia of the organ of Corti had abnormal polarity in Dvl DKO, Lp/Lp and Dvl2−/− Lp/+ embryos.
Figure 5: Shorter and wider cochlear duct and its sensory organ in PCP mutants.
Figure 6: Direct requirement for PCP pathway in extension and PCP of the organ of Corti.

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Acknowledgements

We thank K. Moses, W. Sale, B. Shur and J. Wallingford for discussions during the project and comments on the manuscript; D. Martin, T. Etzel, E. Kothari and J. Zhao for transgenic service; D. Wu for technical advice on inner ear paint fill; R. Apkarian for SEM; J. Saek for hair cell counting; J.E. Johnson for Math1GFP animals; W. Sale for acetylated α-tubulin antibody; the UCSD/NINDS Neuroscience Microscopy Core; and the Developmental Studies Hybridoma Bank for Islet1 antibody. This work is supported by grants from the US National Institute of Health (to A.C., X.L., A.W.-B. and P.C.), the Woodruff Foundation (to X.L. and P.C.) and the American Heart Association (to J.W.).

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Correspondence to Anthony Wynshaw-Boris or Ping Chen.

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Supplementary information

Supplementary Fig. 1

Unidirectional extension of the cochlea and its sensory organ by DiI labeling in vitro. (PDF 65 kb)

Supplementary Fig. 2

Generation of transgenic mice carrying Dvl2-EGFP. (PDF 315 kb)

Supplementary Fig. 3

Postulated radial and medial-lateral intercalation of the organ of Corti during terminal differentiation. (PDF 109 kb)

Supplementary Table 1

Tabulation of decreased length to width ration and hair cell numbers in PCP mutants. (PDF 100 kb)

Supplementary Table 2

Primers used for genotyping and cDNA amplification. (PDF 32 kb)

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Wang, J., Mark, S., Zhang, X. et al. Regulation of polarized extension and planar cell polarity in the cochlea by the vertebrate PCP pathway. Nat Genet 37, 980–985 (2005). https://doi.org/10.1038/ng1622

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