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Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus

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Abstract

Ependymal cells form the epithelial lining of cerebral ventricles. Their apical surface is covered by cilia that beat in a coordinated fashion to facilitate circulation of the cerebrospinal fluid (CSF). The genetic factors that govern the development and function of ependymal cilia remain poorly understood. We found that the planar cell polarity cadherins Celsr2 and Celsr3 control these processes. In Celsr2-deficient mice, the development and planar organization of ependymal cilia are compromised, leading to defective CSF dynamics and hydrocephalus. In Celsr2 and Celsr3 double mutant ependyma, ciliogenesis is markedly impaired, resulting in lethal hydrocephalus. The membrane distribution of Vangl2 and Fzd3, two key planar cell polarity proteins, was disturbed in Celsr2 mutants, and even more so in Celsr2 and Celsr3 double mutants. Our findings suggest that planar cell polarity signaling is involved in ependymal cilia development and in the pathophysiology of hydrocephalus, with possible implications in other ciliopathies.

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Figure 1: Celsr2 is expressed in differentiating ependymal cells but not in choroid plexus.
Figure 2: Celsr2 and Celsr2+3 mutant mice display hydrocephalus.
Figure 3: Ependymal cilia abnormalities in Celsr2 and Celsr2+3 mutant mice.
Figure 4: Ciliogenesis is altered in Celsr2 and Celsr2+3 deficient mice.
Figure 5: Inactivation of Celsr2 and 3 affects polarization and apical positioning of cilia.
Figure 6: Celsr2 and Celsr2+3 deficiency affects fluid flow.
Figure 7: Combined mutation of Celsr2 and Celsr3 causes lethal hydrocephalus.
Figure 8: The cellular distribution of Fzd3 and Vangl2 is perturbed in Celsr2 and Celsr2+3 mice.

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  • 23 May 2010

    In the version of this article initially published online, the subheading ‘Celsr2 mutant mice develop progressive hydrocephalus’ incorrectly appeared twice. In addition, asterisks noting statistical significance in Figure 6d were missing. These errors have been corrected for the print, PDF and HTML versions of the article.

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Acknowledgements

We thank K. Jones for Emx1-Cre mice, G. Meyer for the antibody to SCO-spondin, and K.-A. Nave for NEX-Cre mice. We also thank V. Bonte, I. Lambermont and E. Paitre for technical assistance and M.F. Boulanger, Y. Houbion, M.-J. Vertez and R. Vigneron for help with electron microscopy. This work was supported by grants from the Actions de Recherches Concertées (ARC-186), FRFC 2.4504.01, FRSM 3.4501.07, Interuniversity Poles of Attraction (SSTC, PAI p6/20), the Fondation médicale Reine Elisabeth, the Wallonne and Bruxelloise régions from Belgium and from the Japan Science and Technology Corporation. F.T. is a research associate at the Belgian Fonds National de la Recherche Scientifique.

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Authors and Affiliations

Authors

Contributions

F.T. characterized the Celsr2 mutant allele, studied Celsr2 and Celsr3 expression and carried out histological and immunofluorescence studies; Y.Q. performed SEM and TEM with the help of Y.P.; L.Z. and J.L. studied cilia function in brain slices; K.K. monitored cilia beats and analyzed data with D.S. and T.F.; M.M. provided the Vangl2 antibody and commented on the manuscript; D.S. and P.C. helped with the confocal microscopy and commented on the manuscript; T.U. analyzed the ciliary beat data, provided the Celsr2 antibody and commented on the manuscript; F.T. and A.M.G. designed research, analyzed data and wrote the manuscript.

Corresponding authors

Correspondence to Fadel Tissir or Andre M Goffinet.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1 and 2 and Supplementary Data (PDF 2869 kb)

Supplementary Movie 1

Wild-type cilia beats, “seaweed” type. (MOV 3752 kb)

Supplementary Movie 2

Wild-type cilia beats, “pigeon neck” type. (MOV 3752 kb)

Supplementary Movie 3

Celsr2 mutant cilia beats, “seaweed” type. (MOV 3752 kb)

Supplementary Movie 4

Celsr2 mutant cilia beats, “pigeon neck” type. (MOV 3752 kb)

Supplementary Movie 5

Movement of latex beads in lateral ventricle of wild-type and Celsr2 mutant tissue. (MOV 5949 kb)

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Tissir, F., Qu, Y., Montcouquiol, M. et al. Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus. Nat Neurosci 13, 700–707 (2010). https://doi.org/10.1038/nn.2555

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