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Planar cell polarity breaks bilateral symmetry by controlling ciliary positioning


Defining the three body axes is a central event of vertebrate morphogenesis. Establishment of left–right (L–R) asymmetry in development follows the determination of dorsal–ventral and anterior–posterior (A–P) body axes1,2, although the molecular mechanism underlying precise L–R symmetry breaking in reference to the other two axes is still poorly understood. Here, by removing both Vangl1 and Vangl2, the two mouse homologues of a Drosophila core planar cell polarity (PCP) gene Van Gogh (Vang), we reveal a previously unrecognized function of PCP in the initial breaking of lateral symmetry. The leftward nodal flow across the posterior notochord (PNC) has been identified as the earliest event in the de novo formation of L–R asymmetry3,4. We show that PCP is essential in interpreting the A–P patterning information and linking it to L–R asymmetry. In the absence of Vangl1 and Vangl2, cilia are positioned randomly around the centre of the PNC cells and nodal flow is turbulent, which results in disrupted L–R asymmetry. PCP in mouse, unlike what has been implicated in other vertebrate species, is not required for ciliogenesis, cilium motility, Sonic hedgehog (Shh) signalling or apical docking of basal bodies in ciliated tracheal epithelial cells. Our data suggest that PCP acts earlier than the unidirectional nodal flow during bilateral symmetry breaking in vertebrates and provide insight into the functional mechanism of PCP in organizing the vertebrate tissues in development.

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Figure 1: The Vangl2Δ/Δ; Vangl1gt/gt embryos have the most severe polarity defects.
Figure 2: Laterality defects in the Vangl2Δ/Δ; Vangl1gt/gt embryos.
Figure 3: Randomized ciliary positioning in the Vangl2Δ/Δ; Vangl1gt/gt embryos.
Figure 4: Vangl1 and Vangl2 are required for normal leftward nodal flow.

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We thank members of the Yang laboratory for stimulating discussion; M. Kuehn, A. Kumar and J. Regard for critical reading of the manuscript; J. Fekecs and D. Leja for preparing the graphics; D. Wu for teaching us to dissect the mouse cochlea; and M. Kelley for the anti-Vangl2 antibodies. This study is supported by the intramural research programme of National Human Genome Research Institute.

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Authors and Affiliations



H.S. designed and performed the experiments, generated most of the data in the manuscript, and interpreted and presented the data in figures. J.H. designed and performed some of the experiments, conducted statistical analysis, interpreted the data and put it together in figures. W.C. analysed and maintained the Vangl1 mutant mice. G.E. generated the Vangl1 and Vangl2 mutant mice by performing blastocyst injection and tetraploid aggregation. P.A. and B.G. provided some critical technical support and help in writing the manuscript. Y.Y. designed and supervised the entire project, interpreted all data and wrote the manuscript.

Corresponding author

Correspondence to Yingzi Yang.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1-S7 with legends. (PDF 7259 kb)

Supplementary Movie 1

This movie shows the smooth nodal flow indicated by unidirectional bead movement in a control embryo. The nodal flow was visualized by latex beads in a Vangl2Δ/+;Vangl1gt/+ embryo at E8.0. The time lapse covers a period of about 13 seconds. Movie was acquired at 14 frames per second (fps) and is played back at the same speed. By following the bead movement and tracing the paths with lines in different color, it is evident from the straight and parallel bead paths that the nodal flow in the control embryo is smooth and unidirectional (leftward). (MOV 2918 kb)

Supplementary Movie 2

This movie shows the turbulent nodal flow indicated by abnormal bead movement in aVangl2Δ/Δ;Vangl1gt/gt embryo at E8.0. The movie was taken as described above. It is evident that the unidirectional leftward nodal flow is disrupted as the bead paths contained "knots", abrupt turns and were often crossed with each other. (MOV 3126 kb)

Supplementary Movie 3

This movie shows the beating cilia in the PNC of a control (Vangl2Δ/+; Vangl1gt/+) embryo at E8.0. The time lapse covers a period of about 12 seconds. The movie was acquired at 42 fps and is played back at 10 fps. (MOV 588 kb)

Supplementary Movie 4

This movie shows the beating cilia in the PNC of a Vangl2Δ/Δ;Vangl1gt/gt embryo at E8.0. The cilia in the mutant PNC were beating in the same direction and at the same speed as in the control embryos. (MOV 491 kb)

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Song, H., Hu, J., Chen, W. et al. Planar cell polarity breaks bilateral symmetry by controlling ciliary positioning. Nature 466, 378–382 (2010).

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