Cilia in the nervous system: linking cilia function and neurodevelopmental disorders

Abstract

Purpose of review: Ciliopathies are genetic disorders caused by defects of primary ciliary structure and/or function and are characterized by pleiotropic clinical features. The ciliopathies include several partially overlapping syndromes such as Joubert syndrome, Bardet-Biedl syndrome and Meckel-Gruber syndrome, all of which have pronounced neurodevelopmental features. Here we focus on potential roles of cilia in central nervous system function, to explore how impairments may cause brain malformation and neurodevelopmental disease.

Recent findings: Cilia have long been considered as 'sensory cellular antennae', responding as chemo-sensors, mechano-sensors and thermo-sensors, although their roles in development were not well understood until recently. The surprising finding that disparate syndromes are all due to defects of the primary cilia, along with the recent advances in genetics, has helped elucidate further roles of primary cilia beyond sensory functions. Several molecules that are associated with key signaling pathways have been discovered in primary cilia. These include sonic hedgehog, wingless, planar cell polarity and fibroblast growth factor, which are essential for many cellular processes. Additionally, mutations in 'ciliome' genes have largely shown developmental defects such as abnormal body axis and brain malformation, implying disrupted cilia-related signaling pathways. Accordingly, the emerging theme is that primary cilia may play roles as modulators of signal transduction to help shape cellular responses within the environmental context during both development and homeostasis.

Summary: The link between cilia and signal pathways has become a framework for understanding the pathogenesis of ciliopathies. Despite recent progress in ciliary biology, fundamental questions remain about how cilia regulate neuronal function in the central nervous system. Therefore, investigation of ciliary function in the nervous system may reveal cilia-modulating mechanisms in neurodevelopmental processes, as well as suggest new treatments for disease.

Figure 1. Intraflagellar transporting and signaling pathways within the primary cilium

(a) The protein cargos are transported from the Golgi to the basal body by vesicle trafficking in the cellular cytoplasm. In order to move ciliary cytosolic and membrane proteins, kinesin 2 and dynein 2, motor proteins associating with intraflagellar transport (IFT) complex, travel along the axoneme between the base and the tip of the cilium in an anterograde and retrograde direction respectively. (b) The primary cilium modulates several signal transduction pathways. Sonic hedgehog (Shh) signaling is activated by binding of Shh to patched (Ptc1), releasing smoothened (Smo) and the downstream target gene transcription from inhibition. Canonical wingless (Wnt) signaling through low-density lipoprotein receptor-related protein (LRP)5/6 and Frizzled (Fzd) is inhibited by the primary cilium, whereas noncanonical Wnt signaling [planar cell polarity (PCP) pathway] requires the primary cilium to be activated by Dishevelled (Dvl) interacting with either Fzd or Inversin (Inv)/other PCP components such as Vangl2. Platelet-derived growth factor (PDGF) signaling through PDGF receptor (PDGFR) requires ciliary localization of the receptor to activate downstream targets. In response to fluid flow, calcium signaling is activated through mechanosensing by polycystin-1 (PC1) and polycystin-2 (PC2) localized in the ciliary membrane. , ciliary membrane proteins; , ciliary proteins; , IFT complex; , kinesin 2; , dynein 2; , nonciliary proteins.

Figure 2. Cilia in various types of cells in the brain

(a) Motile cilia anchored to the basal body are present in the ependymal cells lining the ventricle. (b) Neurons contain primary cilia projecting from basal bodies, but the cilium appears buried among the dendrites and axons of adjacent neurons. (c) Schematic diagram of the cilia axoneme cross-section. Motile cilia have 9 + 2 microtubule pair ultrastructure, with inner and outer dynein arms, whereas primary cilia have 9 + 0 microtubule pair ultrastructure, without dynein arms.