Abstract
BackgroundSonic hedgehog (Shh) signaling in the mouse requires the microtubule-based organelle, the primary cilium. The primary cilium is assembled and maintained through the process of intraflagellar transport (IFT) and the response to Shh is blocked in mouse mutants that lack proteins required for IFT. Although the phenotypes of mouse IFT mutants do not overlap with phenotypes of known Wnt pathway mutants, recent studies report data suggesting that the primary cilium modulates responses to Wnt signals.Methodology/Principal FindingsWe therefore carried out a systematic analysis of canonical Wnt signaling in mutant embryos and cells that lack primary cilia because of loss of the anterograde IFT kinesin-II motor (Kif3a) or IFT complex B proteins (Ift172 or Ift88). We also analyzed mutant embryos with abnormal primary cilia due to defects in retrograde IFT (Dync2h1). The mouse IFT mutants express the canonical Wnt target Axin2 and activate a transgenic canonical Wnt reporter, BAT-gal, in the normal spatial pattern and to the same quantitative level as wild type littermates. Similarly, mouse embryonic fibroblasts (MEFs) derived from IFT mutants respond normally to added Wnt3a. The switch from canonical to non-canonical Wnt also appears normal in IFT mutant MEFs, as both wild-type and mutant cells do not activate the canonical Wnt reporter in the presence of both Wnt3a and Wnt5a.ConclusionsWe conclude that loss of primary cilia or defects in retrograde IFT do not affect the response of the midgestation embryo or embryo-derived fibroblasts to Wnt ligands.
Highlights
Recent experiments have provided strong evidence that primary cilia are essential for mammalian Hedgehog signaling
We conclude that loss of primary cilia or defects in retrograde intraflagellar transport (IFT) do not affect the response of the midgestation embryo or embryo-derived fibroblasts to Wnt ligands
Axin2 is expressed normally in IFT mutant embryos To test for a role of primary cilia in Wnt signaling during development, we analyzed the expression of Axin2 in wild-type and mutant midgestation (embryonic day 9.5 (e9.5)) mouse embryos
Summary
Recent experiments have provided strong evidence that primary cilia are essential for mammalian Hedgehog signaling. Inversin protein is enriched in cilia and basal bodies (in addition to the adherens junctions and nucleus [12]), which suggested that cilia might provide an important site for localization of Wnt pathway components. Sonic hedgehog (Shh) signaling in the mouse requires the microtubule-based organelle, the primary cilium. The primary cilium is assembled and maintained through the process of intraflagellar transport (IFT) and the response to Shh is blocked in mouse mutants that lack proteins required for IFT. The phenotypes of mouse IFT mutants do not overlap with phenotypes of known Wnt pathway mutants, recent studies report data suggesting that the primary cilium modulates responses to Wnt signals
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