Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Hedgehog signalling in the mouse requires intraflagellar transport proteins

Nature volume 426, pages 83–87 (2003)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

References

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

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  ADS  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, 10021, New York, USA

    Danwei Huangfu, Aimin Liu, Andrew S. Rakeman, Lee Niswander & Kathryn V. Anderson

  2. Howard Hughes Medical Institute, Weill Graduate School of Medical Sciences, Cornell University, 445 East 69th Street, New York, 10021, New York, USA

    Aimin Liu & Lee Niswander

  3. Neuroscience Program, Weill Graduate School of Medical Sciences, Cornell University, 445 East 69th Street, New York, 10021, New York, USA

    Danwei Huangfu

  4. Molecular Cell and Developmental Biology Program,

    Andrew S. Rakeman

  5. Weill Graduate School of Medical Sciences, Cornell University, 445 East 69th Street, New York, 10021, New York, USA

    Andrew S. Rakeman

  6. Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, 11100 Euclid Avenue, Ohio, 44106, Cleveland, USA

    Noel S. Murcia

Authors
  1. Danwei Huangfu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aimin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew S. Rakeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Noel S. Murcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lee Niswander
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kathryn V. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathryn V. Anderson.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Huangfu, D., Liu, A., Rakeman, A. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003). https://doi.org/10.1038/nature02061

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature02061

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing