Cell Biology Select

Cilia are key subcellular organelles for the coordination of signaling pathways. The importance of cilia is underscored by the number of diseases associated with cilia dysfunction. Here we highlight recent studies on the role of cilia in signaling and disease. Sonic hedgehog (Shh)—one of three vertebrate hedgehog (Hh) proteins—is an important morphogen during development that specifies ventral neural cell types in the neural tube. Shh binds to the transmembrane protein Patched (Ptc1), and this interaction alleviates inhibition of the trans-membrane protein Smoothened (Smo) by Ptc1. Smo then activates the Gli2 transcriptional activator thereby transmitting the Shh signal to the nucleus. In mammals, the way in which Shh inhibits Ptc1 and Ptc1 inhibits Smo is still unclear. Components of primary cilia have been implicated in Hh signaling and several proteins of the Hh pathway are found in cilia. This connection prompted Rohatgi et al. (2007) to examine the role of cilia in Hh signaling in mouse embryonic fibroblasts (MEFs) and a fibroblast cell line. Their results indicate that cilia play a crucial part in relaying the Shh signal. The authors observed that treatment with Shh or a Shh agonist (that binds to and activates Smo) caused Smo to become localized to the primary cilium. In Ptc1-deficient cells, Smo was found in the primary cilium in the absence of Shh. Expression of a fluorescently tagged version of Ptc1—which was observed at the base and shaft of the primary cilium—in the Ptc1-deficient cells caused Smo to leave the cilia. They also observed localization of Ptc1 and Smo at the cilia in embryonic tissues patterned by Shh. A fluorescently labeled Shh fragment colocalized with fluorescently labeled Ptc1 at the cilia in live cells, indicating that these two proteins may interact at the cilium. Treatment with Shh caused the movement of Ptc1 out of the cilia and the appearance of Smo in the cilia. Oxysterols are known to activate the Hh pathway, and Rohatgi et al. now show that this is due to relocalization of Smo to the cilia upon treatment with the oxysterol 20a-hydroxycholesterol. However, in this situation, Ptc1 is still in the cilia, indicating that oxysterols act downstream of Ptc and somehow render Smo insensitive to Ptc1. Further insight into how trafficking into and out of cilia is regulated will contribute to our understanding of how these structures act as signaling organelles. Vierkotten et al. (2007) found a component of the Shh signaling …