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Sec24b selectively sorts Vangl2 to regulate planar cell polarity during neural tube closure

Nature Cell Biology volume 12, pages 41–46 (2010)Cite this article

Abstract

Craniorachischisis is a rare but severe birth defect that results in a completely open neural tube. Mouse mutants in planar cell polarity (PCP) signalling components have deficits in the morphological movements of convergent extension that result in craniorachischisis. Using a forward genetic screen in mice, we identified Sec24b, a cargo-sorting member of the core complex of the endoplasmic reticulum (ER)-to-Golgi transport vesicle COPII, as critical for neural tube closure. Sec24bY613 mutant mice exhibit craniorachischisis, deficiencies in convergent extension and other PCP-related phenotypes. Vangl2, a key component of the PCP-signalling pathway critical for convergent extension, is selectively sorted into COPII vesicles by Sec24b. Moreover, Sec24bY613 genetically interacts with a loss-of-function Vangl2 allele (Vangl2LP), causing a marked increase in the prevalence of spina bifida. Interestingly, the Vangl2 looptail point mutants Vangl2D255E and Vangl2S464N, known to cause defects in convergent extension, fail to sort into COPII vesicles and are trapped in the ER. Thus, during COPII vesicle formation, Sec24b shows cargo specificity for a core PCP component, Vangl2, of which proper ER-to-Golgi transport is essential for the establishment of PCP, convergent extension and closure of the neural tube.

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Figure 1: The mutation in mouse line 811 is Sec24bY613.
Figure 2: Sec24bY613/Y613 embryos have defects in cochlear hair cell development and convergent extension.
Figure 3: Sec24b and Vangl2 genetically interact.
Figure 4: Sec24b strongly enhances the ER export of Vangl2 but not Vangl2 looptail mutants.
Figure 5: Sec24bY613/Y613 embryos show aberrant subcellular localization of Vangl2 in the developing spinal cord in vivo.

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Acknowledgements

We thank J. Nathans, T. Makita, A. Kolodkin, and members of the Ginty laboratory for discussions and critical reading of this manuscript; P. Gros for providing the Vangl2 antibody; J. C. Fromme, B. Kleizen and A. Schindler for Anti-Sec13 and Anti-Sec22 antiserum; C.Chan for recombinant Sec23A/Sec24A and Sec23A/Sec24C; B. Yang and Y. Wu for excellent technical help. This work was funded by NIH grants NS34814 (D.D.G.) and the Johns Hopkins Mind Brain Institute. D.D.G. and R.S. are investigators of the Howard Hughes Medical Institute.

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  1. Janna Merte and Devon Jensen: These authors contributed equally to this work.

Authors and Affiliations

  1. The Solomon H. Snyder Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, 21205, MD, USA

    Janna Merte, Kevin Wright, Sarah Sarsfield & David D. Ginty

  2. Department of Molecular and Cell Biology and Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, 94720, CA, USA

    Devon Jensen & Randy Schekman

  3. Department of Molecular Biology and Genetics and Howard Hughes Medical Institute, Johns Hopkins University, Baltimore, 21205, MD, USA

    Yanshu Wang

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Contributions

J.M. and D.D.G. designed the forward genetic screen. J.M. developed and implemented the screen, identified the novel mouse line with craniorachischisis, did the positional cloning to map the mutation to Sec24bY613, characterized PCP-related phenotypes in the Sec24bY613 mutants and showed that Vangl2LP and Sec24bY613 genetically interact. D.J. did the experiments showing that Sec24bY613 cannot form an oligomer with Sec23, and the COPII vesicle sorting experiments showing that Vangl2 is selectively sorted by Sec24b and that mutant forms of Vangl2 fail to properly sort into these vesicles. K.W. identified and analysed the missexpression of Vangl2 in Sec24bY613 mutant neuroepithelium. Y.W. aided in experimental planning of PCP phenotype analysis and performed some cochlear hair cell orientation analysis. S.S. aided in the implementation of the forward genetic screen that identified Sec24bY613 and the mapping of the point mutation. R.S. conducted experimental design and analysis of the role of Sec24b in the sorting and expression of Vangl2 and Vangl2-mutant proteins. D.D.G. conducted experimental design and analysis of the forward genetic screen, mutation mapping, and mouse phenotypic analysis. J.M. and D.D.G. wrote the manuscript.

Corresponding author

Correspondence to David D. Ginty.

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Merte, J., Jensen, D., Wright, K. et al. Sec24b selectively sorts Vangl2 to regulate planar cell polarity during neural tube closure. Nat Cell Biol 12, 41–46 (2010). https://doi.org/10.1038/ncb2002

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