The role of primary cilia in neuronal function

Abstract

The "ciliopathies" are a newly defined group of disorders characterized by defects in the structure or function of the cellular primary cilium. Patients with these disorders display variably expressive fibrocystic renal disease, retinal blindness, polydactyly, obesity, and brain dysgenesis as well as neurocognitive impairments. Joubert syndrome is a ciliopathy defined by cerebellar vermis hypoplasia, oculomotor apraxia, intermittent hyperventilation, and mental retardation. Recent evidence suggests important roles for the primary cilium in mediating a host of extracellular signaling events such as morphogen, mitogen, homeostatic and polarity signals. Based upon the clinical features of ciliopathies and cilia mediated signaling pathways, the data support a role for the primary cilium in modulating neurogenesis, cell polarity, axonal guidance and possibly adult neuronal function.

Fig. 1

Schematic diagram of primary cilium. Primary cilia lack the central microtubule pair and their cross-section show ‘9+0’ arrangement (inset). Cilia structure and function are maintained by intraflagellar transport (IFT) within primary cilia. The protein cargo is produced in the Golgi apparatus, moves towards the cilium, and binds to the IFT complex. IFT complex/cargo assembly can be transported along microtubules. The anterograde movement (toward the tip of the cilium) of IFT complex/cargo assembly relies on kinesin 2, while dynein 2 transports in the retrograde direction (toward the basal body of the cilium). Functionally, primary cilia are involved in various signaling pathways including Sonic hedgehog (Shh), Wnt, platelet-derived growth factor (PDGF), and G-protein coupled receptor (GPCR). These signaling pathways play important roles in regulating various neuronal functions including cerebellar development, hippocampal neurogenesis, and obesity. Abbreviations: PTCH, Patched 1; PDGFR, Platelet-derived growth factor receptor.

Fig. 2

JS genes implicated in the Shh, Wnt, and PDGFα signaling pathway. ARL13B and INPP5E localize to the cilium, whereas AHI1 and CEP290 localize to the basal body. CEP290, a centrosomal protein, is involved in Rab8 contained vesicle transport and ciliogenesis through its interaction with PCM-1. The disruption of ARL13B causes defects in ciliary structure and Shh signaling. ARL13B is required for body axis formation, renal function, and neural tube patterning. INPP5E plays an essential role in stabilizing cilia in response to serum stimulation, possibly by controlling PDGFα signaling. AHI1 interacts with and facilitates β-catenin (β-Cat) accumulation in the nucleus to positively modulate Wnt signaling. Wnt/β-catenin signaling via AHI1 is essential for maintaining renal homeostasis.