Elsevier

Differentiation

Volume 83, Issue 2, February 2012, Pages S30-S42
Differentiation

Stages of ciliogenesis and regulation of ciliary length

https://doi.org/10.1016/j.diff.2011.11.015Get rights and content

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.

Section snippets

Cilium structure and function

Cilia are microtubule-based organelles that protrude from nearly all human cells. Notable exceptions are epithelia lining the gastrointestinal tract, non-ciliated Clara cells found in the bronchioles, and T lymphocytes. Cilia contain nine sets of microtubule doublets surrounded by a phospholipid membrane. This membrane is topologically continuous with the plasma membrane surrounding the remainder of the cell, but distinct in its lipid and protein composition. A variety of informative reviews

Deciding when to make a cilium: Cell cycle regulation and ciliogenesis

Cilia are found on quiescent cells and on proliferating cells in the G1 phase of the cell cycle. In dividing cells, they are resorbed before S phase or during G2. There appears to be a bidirectional crosstalk between cilium formation and cell division as improper division can result in abnormal ciliogenesis and failure to form a cilium can regulate the cell cycle. For example, overproliferative cancer cell lines generally lack cilia and cells that cannot properly form a cilium undergo

Ciliary length control models

In order to understand the factors that give rise to a steady state ciliary length and what perturbations may break that homeostasis, it is a useful exercise to consider various models of length control that are consistent with existing data and make predictions about untested hypotheses. The simplest model would be that a cell simply produces the exact quantity of flagellar precursor proteins to build a flagellum or a certain length (Fig. 1A). However we know that the availability of

Diseases of abnormal ciliary formation and maintenance

Ciliopathies produce many phenotypes affecting a wide variety of organ systems. These include cystic kidneys (defects in renal cilia), retinal degeneration (photoreceptor outer segment malformation), left–right asymmetry defects (abnormal nodal cilia), infertility (defective sperm and oviduct flagella and cilia), polydactyly (disruption of Hedgehog signaling), obesity (neuronal cilia defects), and airway abnormalities (dysfunctional tracheal motile cilia). Loss of genes required for

Conclusions

Cilia should be considered critical organelles, like any other, necessary for cellular homeostasis. As we have seen, many cellular processes are dependent on proper timing of ciliogenesis or on proper ciliary maintenance (Fig. 2). We have just begun to scratch the surface on how cilia are regulated and many questions remain. For example, the ciliary transition zone is a hotbed of activity and a hub for accumulation of ciliary proteins. It is unclear how activity is coordinated at this region.

Acknowledgments

We apologize to those whose excellent contributions we were unable to include here. This work was funded by the National Institutes of Health F32 GM090562 and R01 GM097017.

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