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Hedgehog signalling in the mouse requires intraflagellar transport proteins


Intraflagellar transport (IFT) proteins were first identified as essential factors for the growth and maintenance of flagella in the single-celled alga Chlamydomonas reinhardtii1. In a screen for embryonic patterning mutations induced by ethylnitrosourea, here we identify two mouse mutants, wimple (wim) and flexo (fxo), that lack ventral neural cell types and show other phenotypes characteristic of defects in Sonic hedgehog signalling. Both mutations disrupt IFT proteins: the wim mutation is an allele of the previously uncharacterized mouse homologue of IFT172; and fxo is a new hypomorphic allele of polaris, the mouse homologue of IFT88. Genetic analysis shows that Wim, Polaris and the IFT motor protein Kif3a are required for Hedgehog signalling at a step downstream of Patched1 (the Hedgehog receptor) and upstream of direct targets of Hedgehog signalling. Our data show that IFT machinery has an essential and vertebrate-specific role in Hedgehog signal transduction.

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Figure 1: Phenotypes of wim and fxo mutants.
Figure 2: Dorso-ventral patterning in polaristm1Rpw, polarisfxo and wim mutant neural tubes.
Figure 3: Ptch1–lacZ expression in single and double mutants.
Figure 4: Dorso-ventral neural patterning in double mutant embryos.


  1. Rosenbaum, J. L. & Witman, G. B. Intraflagellar transport. Nature Rev. Mol. Cell Biol. 3, 813–825 (2002)

    CAS  Article  Google Scholar 

  2. Ma, Y. et al. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of Dispatched. Cell 111, 63–75 (2002)

    CAS  Article  Google Scholar 

  3. Caspary, T. et al. Mouse Dispatched homolog1 is required for long-range, but not juxtacrine, Hh signaling. Curr. Biol. 12, 1628–1632 (2002)

    CAS  Article  Google Scholar 

  4. Murcia, N. S. et al. The Oak Ridge polycystic kidney (orpk) disease gene is required for left–right axis determination. Development 127, 2347–2355 (2000)

    CAS  Google Scholar 

  5. Collignon, J., Varlet, I. & Robertson, E. J. Relationship between asymmetric nodal expression and the direction of embryonic turning. Nature 381, 155–158 (1996)

    ADS  CAS  Article  Google Scholar 

  6. Schimenti, J. C. et al. Interdigitated deletion complexes on mouse chromosome 5 induced by irradiation of embryonic stem cells. Genome Res. 10, 1043–1050 (2000)

    CAS  Article  Google Scholar 

  7. Motoyama, J. et al. Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Dev. Biol. 259, 150–161 (2003)

    CAS  Article  Google Scholar 

  8. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413 (1996)

    ADS  CAS  Article  Google Scholar 

  9. Litingtung, Y. & Chiang, C. Control of Shh activity and signaling in the neural tube. Dev. Dyn. 219, 143–154 (2000)

    CAS  Article  Google Scholar 

  10. Takeda, S. et al. Left-right asymmetry and kinesin superfamily protein KIF3A: new insights in determination of laterality and mesoderm induction by kif3A-/- mice analysis. J. Cell Biol. 145, 825–836 (1999)

    CAS  Article  Google Scholar 

  11. Marszalek, J. R., Ruiz-Lozano, P., Roberts, E., Chien, K. R. & Goldstein, L. S. Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II. Proc. Natl Acad. Sci. USA 96, 5043–5048 (1999)

    ADS  CAS  Article  Google Scholar 

  12. Goodrich, L. V., Milenkovic, L., Higgins, K. M. & Scott, M. P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997)

    CAS  Article  Google Scholar 

  13. Eggenschwiler, J. T., Espinoza, E. & Anderson, K. V. Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature 412, 194–198 (2001)

    ADS  CAS  Article  Google Scholar 

  14. Eggenschwiler, J. T. & Anderson, K. V. Dorsal and lateral fates in the mouse neural tube require the cell-autonomous activity of the open brain gene. Dev. Biol. 227, 648–660 (2000)

    CAS  Article  Google Scholar 

  15. Wang, B., Fallon, J. F. & Beachy, P. A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423–434 (2000)

    CAS  Article  Google Scholar 

  16. Litingtung, Y. & Chiang, C. Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Nature Neurosci. 3, 979–985 (2000)

    CAS  Article  Google Scholar 

  17. Wheatley, D. N., Wang, A. M. & Strugnell, G. E. Expression of primary cilia in mammalian cells. Cell Biol. Int. 20, 73–81 (1996)

    CAS  Article  Google Scholar 

  18. Sisson, J. C., Ho, K. S., Suyama, K. & Scott, M. P. Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway. Cell 90, 235–245 (1997)

    CAS  Article  Google Scholar 

  19. Ray, K. et al. Kinesin-II is required for axonal transport of choline acetyltransferase in Drosophila. J. Cell Biol. 147, 507–518 (1999)

    CAS  Article  Google Scholar 

  20. Han, Y., Kwok, B. H. & Kernan, M. J. Intraflagellar transport is required in Drosophila to differentiate sensory cilia but not sperm. Curr. Biol. 13, 1679–1686 (2003)

    CAS  Article  Google Scholar 

  21. Bale, A. E. Hedgehog signaling and human disease. Annu. Rev. Genom. Hum. Genet. 3, 47–65 (2002)

    CAS  Article  Google Scholar 

  22. Sloboda, R. D. A healthy understanding of intraflagellar transport. Cell Motil. Cytoskeleton 52, 1–8 (2002)

    CAS  Article  Google Scholar 

  23. Kasarskis, A., Manova, K. & Anderson, K. V. A phenotype-based screen for embryonic lethal mutations in the mouse. Proc. Natl Acad. Sci. USA 95, 7485–7490 (1998)

    ADS  CAS  Article  Google Scholar 

  24. Hui, C. C. & Joyner, A. L. A mouse model of Greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nature Genet. 3, 241–246 (1993)

    CAS  Article  Google Scholar 

  25. Cole, T. B., Wenzel, H. J., Kafer, K. E., Schwartzkroin, P. A. & Palmiter, R. D. Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc. Natl Acad. Sci. USA 96, 1716–1721 (1999)

    ADS  CAS  Article  Google Scholar 

  26. Vetter, D. E. et al. Urocortin-deficient mice show hearing impairment and increased anxiety-like behavior. Nature Genet. 31, 363–369 (2002)

    CAS  Article  Google Scholar 

  27. Weiher, H., Noda, T., Gray, D. A., Sharpe, A. H. & Jaenisch, R. Transgenic mouse model of kidney disease: insertional inactivation of ubiquitously expressed gene leads to nephrotic syndrome. Cell 62, 425–434 (1990)

    CAS  Article  Google Scholar 

  28. Farrelly, D. et al. Mice mutant for glucokinase regulatory protein exhibit decreased liver glucokinase: a sequestration mechanism in metabolic regulation. Proc. Natl Acad. Sci. USA 96, 14511–14516 (1999)

    ADS  CAS  Article  Google Scholar 

  29. Howard, P. W. & Maurer, R. A. Identification of a conserved protein that interacts with specific LIM homeodomain transcription factors. J. Biol. Chem. 275, 13336–13342 (2000)

    CAS  Article  Google Scholar 

  30. Sulik, K. et al. Morphogenesis of the murine node and notochordal plate. Dev. Dyn. 201, 260–278 (1994)

    CAS  Article  Google Scholar 

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We thank K. Maxwell and T. Caspary for initial experiments with fxo; N. Lampen for assistance with SEM; J. Eggenschwiler, D. Cole and M. Kernan for sharing unpublished data; C. Sander and B. Reva for discussions about Wim and Polaris protein structures; T. Bestor, T. Caspary, J. Eggenschwiler, M. García-García and J. Lee for comments on the manuscript; E. Robertson, M. Scott and J. Schimenti for mice; and C. Cepko for the Chx10 antibody. Monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank, which was developed under the auspices of the National Institute of Child Health and Human Development and is maintained by The University of Iowa, Department of Biological Sciences. Genome sequence analysis used Ensembl and the Celera Discovery System and associated databases, made possible in part by the AMDeC Foundation. This work was supported by NIH grants to K.V.A. and the Lita Annenberg Hazen Foundation. L.N. is an Investigator of the Howard Hughes Medical Institute.

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Correspondence to Kathryn V. Anderson.

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Huangfu, D., Liu, A., Rakeman, A. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003).

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