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Review
. 2012 Feb;83(2):S30-42.
doi: 10.1016/j.diff.2011.11.015. Epub 2011 Dec 16.

Stages of ciliogenesis and regulation of ciliary length

Prachee Avasthi  1 , Wallace F Marshall
Affiliations
Review

Stages of ciliogenesis and regulation of ciliary length

Prachee Avasthi et al. Differentiation. 2012 Feb.

Abstract

Cilia and flagella are highly conserved eukaryotic microtubule-based organelles that protrude from the surface of most mammalian cells. These structures require large protein complexes and motors for distal addition of tubulin and extension of the ciliary membrane. In order for ciliogenesis to occur, coordination of many processes must take place. An intricate concert of cell cycle regulation, vesicular trafficking, and ciliary extension must all play out with accurate timing to produce a cilium. Here, we review the stages of ciliogenesis as well as regulation of the length of the assembled cilium. Regulation of ciliogenesis during cell cycle progression centers on centrioles, from which cilia extend upon maturation into basal bodies. Centriole maturation involves a shift from roles in cell division to cilium nucleation via migration to the cell surface and docking at the plasma membrane. Docking is dependent on a variety of proteinaceous structures, termed distal appendages, acquired by the mother centriole. Ciliary elongation by the process of intraflagellar transport (IFT) ensues. Direct modification of ciliary structures, as well as modulation of signal transduction pathways, play a role in maintenance of the cilium. All of these stages are tightly regulated to produce a cilium of the right size at the right time. Finally, we discuss the implications of abnormal ciliogenesis and ciliary length control in human disease as well as some open questions.

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Figures

Figure 1
Figure 1. Limiting-precursor and balance-point models for length control
(A) Limiting Precursor model, in which a fixed number of structural subunits (blue squares) contained with the cell (green circle) are incorporated into the final structure thus fixing its length by their initial quantity. (B) Axonemal tubulin dynamics underlying balance-point model. Tubulin subunits (blue squares) are synthesized in the cytoplasm and transported out to the tip of the cilium by intraflagellar transport (orange circles) where they assemble at the tip. Assembly at the tip is balanced by continuous disassembly of subunits from the tip, which are then returned to the cytoplasm. A putative pore or gate regulating entry of ciliary proteins and IFT proteins is indicated by a red dotted line. In this framework, steady-state length is achieved when the rates of assembly and disassembly are equal. (C) Balance point model for length control. Disassembly (red dotted line) is length-independent based on measurements of flagellar resorbtion in the absence of assembly. Assembly is a decreasing function of length because each IFT particle takes longer to move out to the tip as the length increases, and thus delivers cargo less efficiently. Because the number of IFT particles is fixed, independent of length, the overall efficiency of IFT is a decreasing function of length (green curve). The unique length where the two rates balance (blue arrow) is predicted to be the steady-state length of the cilium.
Figure 2
Figure 2. Mechanisms regulating ciliogenesis and ciliary length
(A) Cycle cycle regulators modulate the centrosome cycle to regulate timing of ciliary resorption, centriole maturation, and ciliogenesis. Ciliation inhibits cell cycle progression. (B) Extracellular signals and intracellular kinase cascades alter their own pathways or converge on common second messengers for centriole or ciliary regulation. (C) Remodeling of actin between contractile stress fibers and a cortical network alters conditions hospitable for basal body docking and maintenance at the cell surface. (D) Proteins regulating centriole migration and formation of appendages regulate basal body docking to ciliary vesicles for fusion with the plasma membrane. (E) Large complexes of disease-related transition zone proteins regulate recruitment of ciliary proteins or gate ciliary entry. (F) Direct modification of axoneme by altering stability through acetylation state or assembly/disassembly through IFT tunes ciliary length.
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