Trends in Cell Biology
OpinionPrimary ciliary signaling: links with the cell cycle
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
References (78)
- et al.
Centrioles, centrosomes, and cilia in health and disease
Cell
(2009) - et al.
The cilium: cellular antenna and central processing unit
Trends Cell Biol.
(2017) Centriole deciliation associated with the early response of 3T3 cells to growth factors but not to SV40
Cell
(1979)The resorption of primary cilia during mitosis in a vertebrate (PtK1) cell line
J. Ultrastruct. Res.
(1979)HEF1-dependent Aurora A activation induces disassembly of the primary cilium
Cell
(2007)Ciliopathies: does HDAC6 represent a new therapeutic target?
Trends Pharmacol. Sci.
(2016)Asymmetric inheritance of centrosome-associated primary cilium membrane directs ciliogenesis after cell division
Cell
(2013)- et al.
Chlamydomonas shortens its flagella by activating axonemal disassembly, stimulating IFT particle trafficking, and blocking anterograde cargo loading
Dev. Cell
(2005) Fragmentation of kidney epithelial cell primary cilia occurs by cisplatin and these cilia fragments are excreted into the urine
Redox Biol.
(2019)IFT-cargo interactions and protein transport in cilia
Trends Biochem. Sci.
(2015)
Akt regulates a Rab11-effector switch required for ciliogenesis
Dev. Cell
PI3K class II alpha controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function
Dev. Cell
Anterograde trafficking of ciliary MAP kinase–like ICK/CILK1 by the intraflagellar transport machinery is required for intraciliary retrograde protein trafficking
J. Biol. Chem.
PDGFRαα signaling is regulated through the primary cilium in fibroblasts
Curr. Biol.
Primary cilia-dependent lipid raft/caveolin dynamics regulate adipogenesis
Cell Rep.
Cilia-associated oxysterols activate Smoothened
Mol. Cell
Expression of autotaxin and lysophosphatidic acid receptors increases mammary tumorigenesis, invasion, and metastases
Cancer Cell
An Aurora kinase is essential for flagellar disassembly in Chlamydomonas
Dev. Cell
Pitchfork regulates primary cilia disassembly and left-right asymmetry
Dev. Cell
Ciliogenesis: building the cell’s antenna
Nat. Rev. Mol. Cell Biol.
Cilia in cell-cultured fibroblasts. II. Incidence in mitotic and post-mitotic BHK 21-C13 fibroblasts
J. Anat.
The role of the cilium in normal and abnormal cell cycles: emphasis on renal cystic pathologies
Cell. Mol. Life Sci.
Current topics of functional links between primary cilia and cell cycle
Cilia
Ciliary signalling in cancer
Nat. Rev. Cancer
The primary cilium: a signalling centre during vertebrate development
Nat. Rev. Genet.
Primary cilia and mammalian Hedgehog signaling
Cold Spring Harb. Perspect. Biol.
A mutation in the 3′-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia
Hum. Mol. Genet.
Tubulin acetylation: responsible enzymes, biological functions and human diseases
Cell. Mol. Life Sci.
Nek2 kinase displaces distal appendages from the mother centriole prior to mitosis
J. Cell Biol.
High-resolution characterization of centriole distal appendage morphology and dynamics by correlative STORM and electron microscopy
Nat. Commun.
Neuroepithelial progenitors undergo LGN-dependent planar divisions to maintain self-renewability during mammalian neurogenesis
Nat. Cell Biol.
A cell/cilia cycle biosensor for single-cell kinetics reveals persistence of cilia after G1/S transition is a general property in cells and mice
Dev. Cell
Resorption of organelles containing microtubules
Cytobios
The ubiquitin conjugation system is involved in the disassembly of cilia and flagella
J. Cell Biol.
Flagellar elongation and shortening in Chlamydomonas. IV. Effects of flagellar detachment, regeneration, and resorption on the induction of flagellar protein synthesis
J. Cell Biol.
A role for katanin-mediated axonemal severing during Chlamydomonas deflagellation
Mol. Biol. Cell
Primary cilium loss in mammalian cells occurs predominantly by whole-cilium shedding
PLoS Biol.
Acetylation of microtubules influences their sensitivity to severing by katanin in neurons and fibroblasts
J. Neurosci.
Cilium structure, assembly, and disassembly regulated by the cytoskeleton
Biochem. J.
Cited by (34)
YAP/Aurora A-mediated ciliogenesis regulates ionizing radiation-induced senescence via Hedgehog pathway in tumor cells
2024, Biochimica et Biophysica Acta - Molecular Basis of DiseaseControl of centrosome distal appendages assembly and disassembly
2023, Cells and DevelopmentFunctions of the primary cilium in the kidney and its connection with renal diseases
2023, Current Topics in Developmental BiologyNovel aspects of intra-islet communication: Primary cilia and filopodia
2023, Advances in Biological RegulationSHCBP1 Overexpression Aggravates Pancreatitis by Triggering the Loss of Primary Cilia
2024, DNA and Cell Biology