Environmental and genetic aberrations lead to neural tube closure defects (NTDs) in 1 out of every 1,000 births1. Mouse and frog models for these birth defects have indicated that Van Gogh-like 2 (Vangl2, also known as Strabismus) and other components of planar cell polarity (PCP) signalling might control neurulation by promoting the convergence of neural progenitors to the midline2,3,4,5,6,7,8. Here we show a novel role for PCP signalling during neurulation in zebrafish. We demonstrate that non-canonical Wnt/PCP signalling polarizes neural progenitors along the anteroposterior axis. This polarity is transiently lost during cell division in the neural keel but is re-established as daughter cells reintegrate into the neuroepithelium. Loss of zebrafish Vangl2 (in trilobite mutants) abolishes the polarization of neural keel cells, disrupts re-intercalation of daughter cells into the neuroepithelium, and results in ectopic neural progenitor accumulations and NTDs. Remarkably, blocking cell division leads to rescue of trilobite neural tube morphogenesis despite persistent defects in convergence and extension. These results reveal a function for PCP signalling in coupling cell division and morphogenesis at neurulation and indicate a previously unrecognized mechanism that might underlie NTDs.
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We thank W. Talbot and D. Lyons for sharing their protocol for pharmacological inhibition of cell division, A. Chitnis for useful discussion, and L. Solnica-Krezel, W. Talbot, J. Wallingford, A. Giraldez, D. Prober and J. Rihel for comments on the manuscript. This work was supported by grants from the NIH to A.F.S. and M.M. A.F.S. was a Scholar of the McKnight Foundation for Neuroscience, an Irma T. Hirschl Trust Career Scientist and an Established Investigator of the American Heart Association. B.C. was supported by a long-term fellowship from the Human Frontier Science Program.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
This figure shows transverse sections taken through the anterior trunk of fixed wild-type embryos, ranging from 5-somite to 20-somite stages. The figure illustrates the morphogenesis of the neural plate into a neural tube. (DOC 259 kb)
This figure shows lateral and dorsal views of wild-type, zygotic trilobite, and maternal-zygotic trilobite mutant embryos at 24 hpf. (DOC 125 kb)
This figure depicts the strategy used to generate silberblick;pipetail germ line-replacement chimeras. (DOC 175 kb)
This figure describes the ppt(sk13) allele used in our studies, and shows MZslb;MZppt and MZslb;MZppt+wnt4MO mutant phenotypes at 30hpf. (DOC 218 kb)
This figure shows dorsal views of the neural keel of wild-type and MZtri mutant embryos, and demonstrates ectopic accumulation of MZtri neural progenitor cells. (DOC 165 kb)
This figure shows rescue of the zebrafish Pk1 morphant phenotype through injection of Gfp-Pk mRNA. (DOC 139 kb)
This figure shows images taken from time-lapse movies of neuroepithelial cell behaviour in the neural keel of genetically chimeric embryos, and demonstrates both cell autonomy and non-autonomy of Vangl2 function. (DOC 571 kb)
This figure shows the effects of blocking cell division on wild-type and MZtri embryonic development. Lateral and dorsal views of live embryos are shown, as well as transverse sections through the anterior trunk of shh-stained embryos. (DOC 241 kb)
This table summarizes the results of WT and MZtri transplantation studies into the autonomy of Vangl2 function in regulating the intercalation of neural progenitor cells into the contralateral neuroepithelial layer following mitosis. (DOC 42 kb)
This movie shows cell division in the neural keel of a WT embryo that has been scatter labeled for mGFP. The confocal time lapse covers a period of 21 min, and demonstrates the rapid intercalation the apical neuroepithelial daughter cell into the contralateral neuroepithelial layer following mitosis. (MOV 3480 kb)
This movie shows cell division in the forming neural keel of an MZtri embryo that has been scatter labeled for mGFP. The confocal time lapse covers a period of 53 min, and demonstrates that MZtri neural progenitors fail to re-intercalate into the neuroepithelium following mitosis. (MOV 9014 kb)
This movie shows the neural keel of a WT embryo that has been scatter labeled for Gfp-Pk. The confocal time lapse covers a period of 30 min, and demonstrates the dynamic punctate localization of Gfp-Pk along the anterior membrane of neural progenitor cells. (MOV 3369 kb)
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Ciruna, B., Jenny, A., Lee, D. et al. Planar cell polarity signalling couples cell division and morphogenesis during neurulation. Nature 439, 220–224 (2006). https://doi.org/10.1038/nature04375
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