In mammals, an example of planar cell polarity (PCP) is the uniform orientation of the hair cell stereociliary bundles within the cochlea. The PCP pathway of Drosophila1,2,3,4 refers to a conserved signalling pathway that regulates the coordinated orientation of cells or structures within the plane of an epithelium. Here we show that a mutation in Vangl2, a mammalian homologue of the Drosophila PCP gene Strabismus/Van Gogh, results in significant disruptions in the polarization of stereociliary bundles in mouse cochlea as a result of defects in the direction of movement and/or anchoring of the kinocilium within each hair cell. Similar, but less severe, defects are observed in animals containing a mutation in the LAP protein family gene Scrb1 (homologous with Drosophila scribble). Polarization defects in animals heterozygous for Vangl2 and Scrb1 are comparable with Vangl2 homozygotes, demonstrating genetic interactions between these genes in the regulation of PCP in mammals. These results demonstrate a role for the PCP pathway in planar polarization in mammals, and identify Scrb1 as a PCP gene.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Adler, P. N. Planar signaling and morphogenesis in Drosophila. Dev. Cell 2, 525–535 (2002)
Adler, P. N. & Lee, H. Frizzled signaling and cell-cell interactions in planar polarity. Curr. Opin. Cell Biol. 13, 635–640 (2001)
Taylor, J., Abramova, N., Charlton, J. & Adler, P. N. Van Gogh: a new Drosophila tissue polarity gene. Genetics 150, 199–210 (1998)
Wolff, T. & Rubin, G. M. Strabismus, a novel gene that regulates tissue polarity and cell fate decisions in Drosophila. Development 125, 1149–1159 (1998)
Murdoch, J. N., Doudney, K., Paternotte, C., Copp, A. J. & Stanier, P. Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification. Hum. Mol. Genet. 10, 2593–2601 (2001)
Kibar, Z. et al. Ltap/Lpp1, a mammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail. Nature Genet. 28, 251–255 (2001)
Strong, L. C. & Hollander, W. F. Hereditary loop-tail in the house mouse accompanied by inperforate vagina and with lethal craniorachischisis when homozygous. J. Hered. 40, 329–334 (1949)
Hudspeth, A. J. & Jacobs, R. Stereocilia mediate transduction in vertebrate hair cells (auditory system/cilium/vestibular system). Proc. Natl Acad. Sci. USA 76, 1506–1509 (1979)
Rubel, E. W. in Handbook of Sensory Physiology IX (ed. Jacobson, M.)) 135–237 (Springer, New York, 1978)
Rachel, R. A., Murdoch, J. N., Beermann, F., Copp, A. J. & Mason, C. A. Retinal axon misrouting at the optic chiasm in mice with neural tube closure defects. Genesis 27, 32–47 (2000)
Murdoch, J. N. et al. Circletail, a new mouse mutant with severe neural tube defects: chromosomal localization and interaction with the loop-tail mutation. Genomics 78, 55–63 (2001)
Rachel, R. A., Wellington, S. J., Warburton, D., Mason, C. A. & Beermann, F. A new allele of Gli3 and a new mutation, circletail (Crc), resulting from a single transgenic experiment. Genesis 33, 55–61 (2002)
Murdoch, J. N. et al. Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse. Hum. Mol. Genet. 12, 87–98 (2003)
Hung, N. Y. & Sheng, M. PDZ domains: structural molecules for protein complex assembly. J. Biol. Chem. 277, 5699–5702 (2002)
Mlodzik, M. Planar cell polarization: do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation? Trends Genet. 18, 564–571 (2002)
Park, M. & Moon, R. T. The planar cell-polarity gene stbm regulates cell behaviour and cell fate in vertebrate embryos. Nature Cell. Biol. 4, 20–25 (2002)
Chen, P., Johnson, J. E., Zoghbi, H. Y. & Segil, N. The role of Math1 in inner ear development: uncoupling the establishment of the sensory primordium from hair cell fate determination. Development 129, 2495–2505 (2002)
Hamblet, N. S. et al. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development 129, 5827–5838 (2002)
Bilder, D. & Perrimon, N. Localization of apical epithelial determinants by the baso-lateral PDZ protein scribble. Nature 403, 676–680 (2000)
Darken, R. S. et al. The planar polarity gene strabismus regulates convergent extension movements in Xenopus. EMBO J. 21, 976–985 (2002)
Goto, T. & Keller, R. The planar cell polarity gene strabismus regulates convergence and extension and neural fold closure in Xenopus. Dev. Biol. 247, 165–181 (2002)
Copp, A. J., Checiu, I. & Henson, J. N. Developmental basis of severe neural tube defects in the loop-tail (Lp) mutant mouse: use of microsatellite DNA markers to identify embryonic genotype. Dev. Biol. 165, 20–29 (1994)
Mueller, K. L., Jacques, B. E. & Kelley, M. W. Fibroblast growth factor signaling regulates pillar cell development in the organ of Corti. J. Neurosci. 22, 9368–9377 (2002)
Lanford, P. J. et al. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nature Genet. 21, 289–292 (1999)
Wu, D. K. & Oh, S. H. Sensory organ generation in the chick inner ear. J. Neurosci. 16, 6454–6462 (1996)
We thank J. Jones for assistance with in situ hybridization and C. Woods for technical support. We also thank R. Wenthold, N. Sans, I. Belyantseva, D. Forrest, A. Dabdoub, J. Jones and R. Hertzano for reading an earlier version of this manuscript. This research was supported by funds from the Intramural Programs at NIDCD and NCI.
The authors declare that they have no competing financial interests.
About this article
Cite this article
Montcouquiol, M., Rachel, R., Lanford, P. et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173–177 (2003). https://doi.org/10.1038/nature01618
Experimental Biology and Medicine (2020)
Molecular Cancer (2020)
Mutations associated with human neural tube defects display disrupted planar cell polarity in Drosophila
Live imaging of hair bundle polarity acquisition demonstrates a critical timeline for transcription factor Emx2
Seminars in Cell & Developmental Biology (2020)