Research highlights
Cell signalling: A ciliary sensor
Nature Reviews Molecular Cell Biology 8, 9 (01 September 2007) | doi:10.1038/nrm2243
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SHH induces the delocalization of PTC1 from the primary cilium. In control cells (left), PTC1 (green) induced to high levels colocalizes with primary cilia (red). PTC1 delocalizes from primary cilia after incubation with SHH (right). Nuclei are stained blue. Image courtesy of L. Milenkovic, Department of Developmental Biology, Genetics and Bioengineering, and Howard Hughes Medical Institute, Stanford University School of Medicine, California, USA.
Specialized cell types are covered with small hair-like projections — known as cilia — that assist the movement of fluids over their cell surface. However, most cells possess a single immotile primary cilium that projects into the extracellular space where it functions as a sensor for signalling molecules. Matthew Scott and colleagues now show that the activity of the Hedgehog (Hh) signalling pathway — which controls crucial aspects of development and stem-cell function — is regulated through the transport of key signalling proteins into and out of the primary cilium.
In mammalian cells, the morphogen sonic hedgehog (SHH) binds to its transmembrane receptor patched-1 (PTC1), and this binding abolishes PTC1-mediated inhibition of a second transmembrane protein known as smoothened (SMO). Activated SMO transduces a signal to the nucleus through glioma (GLI) transcription factors. The authors found that SMO is usually absent from primary cilia in mouse fibroblasts. However, upon treatment with SHH, SMO became concentrated in cilia. By contrast, PTC1 became localized to cilia in the absence of SHH but was missing from these structures after incubation with SHH. To investigate if the relocalization of PTC1 and SMO were linked, the authors analysed Ptc1-/- fibroblasts, which show constitutively active SHH signalling. SMO was localized to primary cilia even in the absence of SHH. Reintroduction of PTC1 into Ptc1-/- fibroblasts prevented SMO accumulation in cilia and switched off the expression of GLI-responsive genes. Activation of the Hh signalling pathway therefore requires the reciprocal movement of PTC1 and SMO out of and into primary cilia, respectively.
The mechanisms by which signalling components are transported into and out of cilia are unknown, but the authors found that treatment of cells with oxysterols (which also activate Hh signalling) caused the localization of SMO into primary cilia. This finding is intriguing because PTC1 has a sterol-sensing domain that could function to regulate oxysterols or related molecules as second messengers.
...primary cilia are specialized antennae for detecting signalling molecules...
This study supports the view that primary cilia are specialized antennae for detecting signalling molecules. Whether the transport of signalling components into and out of cilia represents a generalized mechanism for regulating other ciliary-dependent signalling pathways remains to be seen.
