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Review
. 2021 Feb:110:70-88.
doi: 10.1016/j.semcdb.2020.07.013. Epub 2020 Jul 31.

Primary cilia biogenesis and associated retinal ciliopathies

Holly Y Chen  1 , Ryan A Kelley  2 , Tiansen Li  2 , Anand Swaroop  3
Affiliations
Review

Primary cilia biogenesis and associated retinal ciliopathies

Holly Y Chen et al. Semin Cell Dev Biol. 2021 Feb.

Abstract

The primary cilium is a ubiquitous microtubule-based organelle that senses external environment and modulates diverse signaling pathways in different cell types and tissues. The cilium originates from the mother centriole through a complex set of cellular events requiring hundreds of distinct components. Aberrant ciliogenesis or ciliary transport leads to a broad spectrum of clinical entities with overlapping yet highly variable phenotypes, collectively called ciliopathies, which include sensory defects and syndromic disorders with multi-organ pathologies. For efficient light detection, photoreceptors in the retina elaborate a modified cilium known as the outer segment, which is packed with membranous discs enriched for components of the phototransduction machinery. Retinopathy phenotype involves dysfunction and/or degeneration of the light sensing photoreceptors and is highly penetrant in ciliopathies. This review will discuss primary cilia biogenesis and ciliopathies, with a focus on the retina, and the role of CP110-CEP290-CC2D2A network. We will also explore how recent technologies can advance our understanding of cilia biology and discuss new paradigms for developing potential therapies of retinal ciliopathies.

Keywords: CEP290; Ciliogenesis; Intracellular transport; Photoreceptor; Retinal degeneration; Sensory cilia.

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Figures

Fig. 1.
Fig. 1.
The architecture of the general primary cilium (left) and the photoreceptor outer segment (right). The primary cilium consists of a ciliary membrane and an axoneme. The ciliary membrane is continuous with the plasma membrane but differs in compositions to regulate diverse signaling pathways. In most mammalian cells, the plasma membrane invaginates at the base of the axoneme, forming the ciliary pocket for endocytosis and docking of intraflagellar transport particles. The axoneme elongates from the basal body (BB), which is the mature mother centriole with distal appendages and subdistal appendages. Cross-section diagrams at different positions of the primary cilium with a doublet (axoneme) (“9 + 0” configuration), doublet with Y-links (transition zone), and triplet microtubule structure (basal body) are shown in upper A, B, and C insets, respectively. In motile cilia, the axoneme displays “9 + 2” configuration, with an additional pair of microtubules in the center (Lower A inset). Photoreceptors feature a gradual doublet (base) to singlet (tip) microtubule transformation in the ciliary axoneme [125]. Photoreceptors harbor distinct features to accommodate their sensory function: the outer segment contains tightly packed discs with phototransduction machineries to efficiently capture photons; the inner segment possesses the endoplasmic reticulum, Golgi apparatus, and a large number of mitochondria to meet the high energy demand and biosynthetic needs of the photoreceptors; the ciliary rootlet anchors the BB to the inner segment to stabilize the outer segment.
Fig. 2.
Fig. 2.
Centriole and cilium biogenesis. (A) Regulation of centriole biogenesis during the cell cycle. In the G1/S phase of proliferating cells, assembly of new centrioles are initiated on both the mother centriole and the daughter centriole, creating two mother-daughter centriole pairs. The newly formed centrioles elongate throughout the G2 phase. In the late G2 phase, the daughter centriole from the previous cell cycle acquires distal appendages and subdistal appendages by sequential recruitment of their structural components. Subdistal appendages anchor microtubules and facilitate the formation of the pericentriolar material. To initiate the M phase, the two pairs of centrosomes separate, migrate to the opposite poles of the cells and establish bipolar spindles. Upon exit from cell cycle, the mother centriole docks to the plasma membrane by distal appendages for cilium assembly in response to specific developmental and/or environmental signals. (B) Intracellular pathway of cilium biogenesis. Ciliogenesis is initiated by docking of preciliary vesicles from the Golgi apparatus and recycling endosomes to distal appendages. These vesicles subsequently merge to form a large ciliary vesicle containing machineries for the maturation of the mother centriole and the trafficking of nascent cilia. Upon CP110 removal, the intraflagellar transport (IFT) complexes (IFT-A, pink oval and IFT-B, blue oval) and motor proteins (kinesin-2 motors, red ball and dynein-2 motors, purple ball) are recruited to distal appendages. The transition zone emerges shortly after the recruitment of IFT machineries and is characteristic of the Y-links. The ciliary axoneme elongates and the ciliary membrane extends with the transport of ciliary proteins and building blocks, forming the ciliary sheath. Fusion of the ciliary sheath with the plasma membrane exposes the primary cilia to the external environment.
Fig. 3.
Fig. 3.
Intraflagellar transport (IFT) of the general primary cilium (A) and photoreceptor outer segments (B). A schematic of the base of primary cilium is shown at (C). The IFT machineries are composed of the microtubule motors (kinesins and dyneins), IFT complex (A and B) and accessory proteins (e.g. TULP3, the BBSome). Most ciliary proteins are trafficked to the base of the primary cilia from the post-Golgi network through microtubules in vesicles with the accessory proteins (green oval), which serve as membrane adaptors for specific cargo proteins and IFT complexes. Complex A (pink oval) and complex B (blue oval) move along the microtubule together, yet they have distinct biochemical constituents and functions. Complex B interacts with plus end-directed kinesin-2 motors (red ball) and participates in anterograde transport from the ciliary base to the tip, which is essential for cilia assembly and maintenance. Complex A binds to a minus end-directed motor cytoplasmic dynein-2 (purple ball), which is responsible for retrograde IFT to move cargo proteins from the ciliary tip to the base. In photoreceptors with constant and rapid renewal of the outer segment, besides the conventional pathway by IFT machineries, highly enriched phototransduction proteins (e.g. rhodopsin) can also be transported through recycling endosomes.
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