The primary cilium as a cellular signaling center: lessons from disease

Abstract

Genetic diseases known as ciliopathies have recently entered the limelight, placing new importance on a previously mysterious organelle: the primary cilium. Mutations affecting the primary cilium in both humans and animal models can lead to a plethora of distinct phenotypes including retinal degeneration, kidney cysts, and brain malformations. New findings are quickly lending insight into the functions of this cellular extension that seems to be especially important in modulation of subcellular signaling cascades at various stages of development and adult homeostasis.

Figure 1

Intraflagellar transport within the primary cilium. Kinesin 2 (with its major component Kif3a) transports cargo in an anterograde direction toward the tip of the cilium, while dynein heavy chain 2 (Dnchc2) travels in the retrograde direction toward the base of the cilium. Membrane cargo, like rhodopsin, is first loaded into a vesicle and transported to the basal body from the golgi by dynein 1. Vesicles then fuse with the cilia membrane and membrane bound cargo is transported along the ciliary length by Kif3a and dynein 2. Major components of this process include Rab8 as well as several ciliopathy genes, particularly the BBS proteins. Inset: schematic of a primary cilium cross-section revealing 9+0 architecture.

Figure 2

Various signaling cascades converge at the cilium. (a) Sonic hedgehog (Shh) signaling depends upon translocation of smoothened (Smo) into the primary cilium (a process involving β-arrestins [55]) following binding of Shh to its receptor patched (Ptch) in order to activate Gli transcription factors from the repressor form (GliR) to the activator form (GliA). (b) PDGF signaling through PDGFRαα requires localization of the receptor within the primary cilium to activate MEK/ERK signaling. MEK itself is also localized to the primary cilium. (c) Although not well understood, noncanonical Wnt signaling (planar cell polarity, PCP) also requires the primary cilium and the basal body. Dishevelled (Dvl) activation through Frizzled 3 or 6 (Fzd3/6) leads to cell polarity determination as well as cytoskeletal rearrangements associated with PCP through interaction with Inversin (Inv, NPHP2) and the PCP component Vangl2. Vangl2 itself has also been localized to the primary cilium. (d) Canonical Wnt signaling is inhibited by the primary cilium through regulation of Dvl by CK1δ as well as proteasomal regulation of β-catenin at the basal body. Additional potential regulatory mechanisms are likely to exist as well. (e) Calcium signaling is activated by bending of the cilium in response to fluid flow through mechanosensation by polycystin-1 (PC1) and TRPV4 that form a complex with the calcium ion channel polycystin-2 (PC2). Calcium influx leads to further stimulation of calcium release from intracellular pools and activation of downstream signaling including cAMP-dependent MEK/ERK signaling [56]. (f) Additional signaling cascades implicated at the cilium include G-protein-coupled receptor (GPCR) signaling [57] and extra-cellular matrix (ECM) receptors [58].

Figure 3

The primary cilium as a signaling hub. (a) Cilia projecting into fluid-filled luminal spaces are positioned to respond to signals and fluid flow within the tubule lumen in order to activate signaling cascades such as calcium signaling, as shown in the inset. (b) The neuronal cilium however appears buried among the dendrites and axons of surrounding neurons implicating an alternative rationale for its presence. One model is that the cilium is positioned next to the nucleus such that components of signaling cascades like the Shh pathway (inset) may be concentrated within the cilium in order to faithfully relay messages. Thus, the cilium acts as a concentrator of signaling components, or a signaling hub. Background images are immunostaining within renal tubules or cultured hippocampal neurons.