PerspectiveCell Signaling

A Ciliary Signaling Switch

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Science  20 Jul 2007:
Vol. 317, Issue 5836, pp. 330-331
DOI: 10.1126/science.1146180

Many people are familiar with motile cilia, the cellular, hairlike projections whose beating generates fluid flow that removes particles from our respiratory tract or help oocytes pass through the fallopian tube. Appreciation is now growing for primary cilia, the nonmotile counterparts, present as a single copy on the surface of most cell types in our body. Defects in primary cilia have been linked to disease, and we now know that they function as unique antenna-like structures, probing the extracellular environment for molecules that are recognized by the receptors they bear. This sensory function allows primary cilia to coordinate numerous intercellular signaling pathways that regulate growth, survival, and differentiation of cells during embryonic development and maintenance of healthy tissues (1). On page 372 of this issue, Rohatgi et al. (2) further define the role of primary cilia in regulating the response of cells to Sonic hedgehog (Shh), a secreted protein that constitutes one of the most fundamental and highly conserved signaling systems in vertebrate development (3). Regulated movement of key proteins into and out of the cilium creates a sophisticated switch by which cells can turn this powerful signaling on and off.

Shh is one of three paralogous vertebrate proteins [related to the invertebrate Hedgehog (Hh) protein] that binds to the transmembrane protein Patched (Ptc) at the cell surface. Upon binding, Shh abolishes the inhibitory effect of Ptc on another transmembrane protein, Smoothened (Smo). This relief from inhibition allows Smo to transduce a signal to the nucleus via glioma (Gli) transcription factors, triggering the expression of specific genes. This general scheme is well established; however, there are many unresolved questions about the regulated interaction between separate components of the pathway, and it is unclear how Shh-Ptc interaction increases Smo signaling activity.

Previous work has shown that primary cilia are essential for Shh signaling. Mutations in genes encoding proteins essential for cilia assembly, such as the intraflagellar transport proteins (4), result in dysfunctional Shh signaling and severe developmental disorders in mammals (5). Further, several components of the Shh pathway specifically localize to the tip or base of the primary cilium (6-9), including Gli transcription factors and proteins that regulate Gli activity at the cilium tip. Localization of Smo to the primary cilium increases when a cell is stimulated with Shh (7), indicating that Shh-mediated generation of active forms of the Gli transcription factors takes place in the cilium. Rohatgi et al. now show that Ptc localizes to the primary cilium and that Shh binds to Ptc when it is in this location. In addition, the authors show that the unique and concerted movement of Ptc out of, and Smo into, the primary cilium constitutes a cellular signaling switch responsive to Shh (see the figure).

A ciliary switch.

The primary cilium emanates as a solitary organelle from most cells in our body. (Left) In the absence of Shh, Ptc translocates to the primary cilium and blocks ciliary localization of Smo. Transcription factors (Gli) are degraded or processed to repressors (GliR). (Right) Upon binding of Shh to Ptc in the cilium, Ptc leaves, and Smo enters, the cilium. This switch may be controlled by oxysterols released from the cilium membrane by Ptc. Gli is processed to an activator form (GliA).

Why does Ptc localize to the primary cilium? There are several obvious advantages. The cilium provides a much smaller surface area over which to integrate a signal. Because the cilium protrudes from the main cell body, Ptc has a greater opportunity to sense gradients of Shh molecules in areas further removed from the general cell surface. For example, during early embryonic development, the directed movement of Shh-containing lipoprotein particles is thought to break left-right body symmetry in vertebrates (10). In this scenario, rotating cilia, present on cells in a region called the embryonic node, generate a leftward flow of fluid that directs movement of the particles to the left side of the developing embryo. The particles subsequently fragment, and released Shh molecules are sensed by primary cilia, which activates a signaling cascade in the appropriate tissue that helps define the left-right body plan.

Another important question concerns how the regulated trafficking of Ptc and Smo in primarily cilia is achieved. For Ptc, the answer is still unclear, but Rohatgi et al. demonstrate that addition of oxysterols, which regulate responsiveness to Shh and activate Hh signaling (3), cause Smo (harbored in intracellular vesicles) to move into the cilium and activate Shh signal transduction, while Ptc also remains in the cilium. This finding supports their conclusions that oxysterols make Smo insensitive to the inhibitory effects of Ptc, and that release of oxysterols from the cell membrane regulates Smo trafficking. Ciliary membranes are rich in cholesterol, the precursor of oxysterols. Ptc may control the release of oxysterols from the cholesterol-rich membrane of the primary cilium. The receptor contains a sterol-sensing domain and is highly homologous to Niemann-Pick C1 protein, which is important for cellular cholesterol trafficking (11). Oxysterols may affect Smo localization, directly or indirectly, by masking or unmasking a ciliary targeting motif in the cytoplasmic domain of Smo. One mutation in this domain prevents cilia localization and thus Shh signaling, whereas another mutation increases ciliary localization of Smo and supports constitutive activation of the Shh signaling pathway (7, 9). Moreover, lipid rafts—membrane regions enriched in sterols—may promote the continuous ciliary targeting and/or retention of specific signal components (1), such as Ptc and Smo, in response to Shh signaling.

The concerted action of Shh molecules and oxysterols in the primary cilium may constitute a unique cellular switch between activation and inactivation of the Shh pathway during development and control of tissue homeostasis. Analogously, the protein inversin, which also localizes to primary cilia, functions as a molecular switch between two signaling pathways controlled by the secreted protein Wnt, another fundamental and conserved system that controls development (12). The next challenges are to define the precise molecular mechanisms that underlie the Shh cellular switch, to determine how primary cilia function as specialized organelles that integrate positive and negative inputs on transcription factor (Gli) activity, and to discover how these mechanisms may interact with other signaling events, such as Wnt signaling, in human health and disease.

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