The primary cilium as a complex signaling center

Abstract

Respect for the primary cilium has undergone a remarkable renaissance over the past decade, and it is now thought to be an essential regulator of numerous signaling pathways. The primary cilium's functions range from the movement of cells and fluid, to sensory inputs involved with olfaction and photoreception. Disruption of cilia function is involved in multiple human syndromes collectively called 'ciliopathies'. The cilium's activities are mediated by targeting of receptors, channels, and their downstream effector proteins to the ciliary or basal body compartment. These combined properties of the cilium make it a critical organelle facilitating the interactions between the cell and its environment. Here, we review many of the recent advances contributing to the ascendancy of the primary cilium and how the extraordinary complexity of this organelle inevitably assures many more exciting future discoveries.

Figure 1. Cilia structure

The nine peripheral microtubule doublets of the axoneme form the backbone of the appendage while the basal body at the base is utilized as a template. The axoneme is sheathed in the cilia membrane, which is distinct from the cell membrane. Structures at the base of the cilium such as the transition fibers and the basal body are important for regulating the protein content of the cilia membrane. The inset shows a cross section of the microtubule arrangement of two axoneme microtubule ultra-structures: 9+2 found in most motile cilia and 9+0 found in primary cilia.

Figure 2. Mechanosensory renal cilia

Primary cilia of renal tubule cells act as mechanosensors of fluid flow and possibly facilitate cell- cell communication. In the absence of flow (left), the carboxyl-terminus of polycystin-1 (PC1) is cleaved. The PC1 carboxy-terminal peptide has been detected the nucleus where it is associated with STAT6 and P100 transcriptional regulation. Proteolytic processing of PC1 (right) does not occur in the presence of fluid flow. Polyductin/fibrocystin (left) also undergoes proteolytic processing where the amino-and carboxy-terminal regions remain attached. The amino-terminal ectodomain of polyductin possibly also undergoes shedding. Thus secretion from the cilium may have important functions in paracrine signaling (right). The carboxy-terminal region of PD has been detected in the nucleus, but its function is not known. In the presence of flow (right) calcium enters the cell in response to deflection of the cilium. This calcium signal is dependent on both PC1 and PC2 in the cilium, however it remains unclear how dysregulation of this calcium signaling may lead to cyst formation.

Figure 3. Modified sensory cilia

The outer segment of photoreceptors (A), an elaborate array of membrane discs, in which light detection takes place is connected to the photoreceptor cell by a connecting cilium. The light detecting protein machinery must past through the connecting cilium on its way to the outer segment. (B) In the olfactory sensory neuron of vertebrates, a dendrite ends in a dendritic knob from which olfactory cilia originate. There are several cilia per neuron which protrude into the mucus layer where odorants bind to receptors. (C) Upon odorant receptor binding to the olfactory G-protein coupled receptor (receptor) the G-protein (G_olf) is activated producing cAMP. The cAMP then causes the cyclic nucleotide gated ion channels to open and subsequently effect Cl⁻ channels then potentiating a depolarization of the OSN.

Figure 4. Hedgehog signaling and the cilium

The Hedgehog (Hh) pathway in vertebrates utilizes the cilium as a signaling compartment. In the absence of the Hh ligand (A), the receptor Ptch resides in the cilium and through an unknown mechanism inhibits the transmembrane protein Smo. In the absence of ligand, the repressor forms of the Gli transcription factors inhibit Hh responsive gene transcription, while Gli activator is maintained in the cilia via Sufu binding.(B) Upon Hh binding, Ptch translocates out of the cilia membrane and its inhibition of Smo is alleviated. Activated Smo translocates into the cilia membrane and through unknown mechanisms the Gli activators translocate to the nucleus and activate Hh responsive gene expression.

Figure 5. Wnt signaling and the cilium

The cilium/basal body may function as a regulatory switch to control the balance between the canonical and noncanonical Wnt pathways. In the canonical pathway (A, left), a Wnt ligand binds to the co-receptors Frizzled and LRP. This inhibits the activity of the β-catenin destruction complex possibly through the Dishevelled (Dvl) protein and leads to stabilization of β-catenin., which accumulates in the nucleus and with LEF and TCF activates target genes. In the noncanonical pathway (A, right), Wnt binds to a frizzled receptor, independent of LRP. This activates a membrane form of Dvl which regulates downstream targets. The noncanonical Wnt signal activates Inversin, which resides in multiple locations in the cell including the cilium or at the base of the cilium. Inversin induces the degradation of cytoplasmic but not the membrane form of Dvl. In a ciliated cell (A), both the canonical and noncanonical pathways are operative and the strength of the canonical pathway (A right) is thought to be influenced by the noncanonical Wnt pathway (A, left). In the absence of cilia (B), the model would suggest that noncanonical pathway is unable to efficiently antagonize the activity of the canonical.