Trends in Cell Biology
Volume 31, Issue 12, December 2021, Pages 954-964
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Opinion
Primary ciliary signaling: links with the cell cycle

https://doi.org/10.1016/j.tcb.2021.07.009Get rights and content

Highlights

  • Primary cilia are generally assembled in G0/G1 phase, and disassembled before mitosis, in cells synchronized by serum starvation and restimulation. However, asynchronous cells and mouse tissues display the remaining cilia in early mitosis, which plays important roles in both ciliary reassembly following cell division and the fate of daughter cells.

  • Aurora A plays important roles not only in the mitotic process but also in several aspects of primary ciliary dynamics, such as ciliary disassembly and suppression of ciliogenesis.

  • Extracellular mitogens participate in ciliary assembly, maintenance, and disassembly through receptor tyrosine kinases and lysophosphatidic acid (LPA) receptors (LPARs).

  • The LPA/LPAR signaling pathway is a critical factor to induce ciliary disassembly and cell cycle entry in response to serum restimulation.

  • Primary cilia control several signal transduction pathways, not only by serving as signaling hubs but also by modulating lipid rafts around the ciliary base.

Primary cilia are solitary, microtubule-based structures emanating from the surface of most vertebrate cells. Although it is understood that ciliary assembly and disassembly both depend upon and impact cell cycle progression, critical mechanistic details of these links remain unresolved. Accumulating evidence shows that the signaling pathways downstream of receptor tyrosine kinases and lysophosphatidic acid receptors control the dynamics of primary cilia. It has also become clear that primary cilia not only serve as signaling hubs but also regulate the composition of the surrounding membrane, which is likely to affect the response to growth factors. Here, we overview recent advances in understanding the interplay between primary cilia and the cell cycle, with a focus on growth factor signaling pathways.

Section snippets

What mechanisms connect ciliogenesis and the cell cycle?

The primary cilium is an antenna-like organelle built upon a membrane-anchored basal body (see Glossary) [1., 2., 3.]. The cell cycle dependence of ciliary assembly and disassembly was first suggested almost 50 years ago [4., 5., 6.]. Ciliary assembly is generally observed in G1 or following cell cycle exit in the G0 phase in response to serum starvation, whereas ciliary disassembly is either accompanied or triggered by cell cycle re-entry upon restimulation with serum. Specifically, ciliary

Primary ciliary dynamics and the cell cycle

Primary cilia are dynamic organelles whose assembly and disassembly are tightly connected with cell cycle progression. Generally, ciliary assembly can be induced in the G0/G1 phase using serum starvation to synchronize cell cultures, whereas culture in serum-supplemented medium triggers ciliary disassembly (Figure 1A). Using synchronization of several cell types, including human retinal pigment epithelial (RPE1), murine inner medullary collecting duct 3 (IMCD3), and NIH3T3 cells, it has been

Mitotic ciliary remnants

Primary ciliary disassembly is thought to be a prerequisite for mitosis, facilitating the participation of the centrosome to establish spindle poles and thereby ensure appropriate chromosome segregation (Figure 1A); however, it is unclear whether any remaining cilia affect mitotic entry or the subsequent events. Recently, two groups independently showed that the distal appendages (DAs) of centrioles play a critical role in ciliary disassembly before mitosis [16,17]. During G2/M transition,

Resorption and shedding of primary cilia

Cell cycle–linked ciliary disassembly appears to occur via resorption, in which the axoneme is gradually depolymerized and the ciliary contents are incorporated into the cell body. In Chlamydomonas, cilia are also resorbed into the cell body before cell division. However, conditions of stress or pharmacological induction can also trigger the rapid removal of cilia through whole-cilium shedding, in which the ciliary membrane and axoneme are excised near the base and released from the cell (

Suppression of primary ciliary assembly in proliferating cells

AURKA is functionally activated by numerous partners according to the circumstances (Box 1). Under serum-fed conditions, trichoplein directly binds and activates AURKA at centrioles [30]. Knockdown of trichoplein or AURKA induces ciliogenesis and G0/G1 arrest in RPE1 cells even in the presence of serum. However, in cells whose ciliogenesis is blocked by depletion of essential ciliogenic factors, such as intraflagellar transport (IFT) component proteins [31,32] (Box 2), trichoplein codepletion

EGFR suppresses ciliogenesis

As mentioned above, trichoplein suppresses ciliogenesis by activating the centriolar AURKA in the presence of serum [30]. During serum starvation–induced ciliogenesis, trichoplein is polyubiquitinated by a KCTD17-Cullin 3 E3 ubiquitin ligase complex (CRL3KCTD17) and degraded in a proteasome-dependent manner [40,41] (Figure 2A). In contrast, ubiquitin-specific protease 8 (USP8) that is phosphorylated and activated by epidermal growth factor receptor (EGFR) counteracts CRL3KCTD17-mediated

New insight into ciliary function

Accumulated evidence reveals that numerous signaling modules are targeted to primary cilia, where they transduce signals in a cilia-dependent manner [59]. For example, PDGFRαα is enriched in serum-starved NIH3T3 cells and MEFs and transduces mitogenic signaling through Akt and the MEK/ERK pathway in a cilia-dependent fashion [60]. Moreover, post-translational modification of ciliary tubulin also affects ciliary function [61]: A recent study showed that under conditions of shear stress and

Concluding remarks

Accumulated evidence indicates that the persistent presence of longer cilia suppresses cell cycle re-entry and proliferation and might be relevant to frequent loss of cilia in tumor cells; indeed, a mechanism for this phenomenon has begun to emerge. It is becoming evident that cilia modulate the composition of the membrane around the ciliary base to control signal transduction (Figure 3). The full impact of these primary cilia-driven signal changes remains unclear, but understanding how they

Acknowledgments

This work was supported in part by the Japan Society for the Promotion of Science KAKENHI (20H03448 to K.K. and 21H02696 to M.I.), the Takeda Science Foundation (to K.K. and M.I.), and the Naito Foundation (to M.I.). We thank Edanz (http://jp.edanz.com/ac) for editing a draft of the manuscript.

Declaration of interests

The authors declare no competing interests.

Glossary

Asymmetric cell division
generates two daughter cells with different cell fates. Asymmetric division of stem cells gives rise to one cell with the same potency (self-renewal) and another that is committed to lineage-specific differentiation.
Basal body
formed from the mother centriole and a number of additional proteins, this serves as a nucleation site for the growth of ciliary axoneme microtubules.
Distal appendages (DAs)
pinwheel-like structures protruding from the distal end of the mother

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