Primary Cilia in Brain Development and Diseases

Abstract

The primary cilium, a sensory appendage that is present in most mammalian cells, plays critical roles in signaling pathways and cell cycle progression. Mutations that affect the structure or function of primary cilia result in ciliopathies, a group of developmental and degenerative diseases that affect almost all organs and tissues. Our understanding of the constituents, development, and function of primary cilia has advanced considerably in recent years, revealing pathogenic mechanisms that potentially underlie ciliopathies. In the brain, the primary cilia are crucial for early patterning, neurogenesis, neuronal maturation and survival, and tumorigenesis, mostly through regulating cell cycle progression, Hedgehog signaling, and WNT signaling. We review these advances in our knowledge of primary cilia, focusing on brain development, and discuss the mechanisms that may underlie brain abnormalities in ciliopathies.

Figure 1

Structure of primary cilia. A: Immunofluorescence image of primary cilia (arrows) extending from neural stem cells cultured from embryonic mouse brains. Cilia are labeled by anti-ARL13B antibody (green), and nuclei are stained by DAPI (magenta). B: Schematic of the structure of the primary cilium. The basal body, a modified mother centriole that contains a ring of nine microtubule triplets, attaches to the plasma membrane via transition fibers. The transition fibers recruit components of intraflagellar transport (IFT), a bidirectional transport system that operates between the ciliary tip and base. IFT builds and maintains cilia by supplying axonemal components to the tip of the axoneme, a ring of nine microtubule doublets that grow from the basal body. Kinesin II and cytoplasmic dynein II motors drive anterograde IFT (from the base to the tip) and retrograde IFT, respectively. IFT motors bind to cargoes via IFT particles, adaptor complexes composed of IFT A and IFT B. The BBSome, a complex of proteins that are mutated in Bardet-Biedl syndrome, coordinates the assembly of the IFT complex at the ciliary base and its recycling at the tip. The BBSome also functions as an IFT adaptor for some cargoes, including membrane proteins. The proximal end of the cilium above the basal body is the transition zone, which is defined by the presence of Y-shaped link fibers that connect axonemes with the ciliary membrane. The Y-shaped link includes two interacting complexes composed of proteins that are mutated in ciliopathies. The transition zone, together with the transition fibers, forms the ciliary gate that regulates the trafficking of ciliary components. The ciliary gate, IFT, and BBSome, by actively controlling ciliary trafficking, establish and maintain the cilium as a compartment with constituents distinct from the rest of the cell. Mutations affecting ciliary structure and function, including the ciliary gate, IFT, and BBSome, result in ciliopathies, a group of developmental and degenerative diseases that can affect almost all organs and tissues. At right are schematic drawings of cross sections of the cilium at different levels indicated with dashed lines: ciliary axoneme (1), transition zone (2), distal end of the basal body with transition fibers (3), and basal body (4). Scale bar = 5 μm (A).