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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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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initial experiments with fxo; N. Lampen for assistance with SEM; J. Eggenschwiler, D. Cole and M. Kernan for sharing unpublished data; C. Sander and B. Reva for discussions about Wim and Polaris protein structures; T. Bestor, T. Caspary, J. Eggenschwiler, M. García-García and J. Lee for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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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.


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