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Mechanisms of cilia disassembly. Major signaling cascades and molecular players regulating the process of cilia disassembly. Mechanisms of cilia disassembly. Major signaling cascades and molecular players regulating the process of cilia disassembly.
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The primary cilium, an antenna-like structure that protrudes out from the cell surface, is present in most cell types. It is a microtubule-based organelle that serves as a mega-signaling center and is important for sensing biochemical and mechanical signals to carry out various cellular processes such as proliferation, migration, differentiation, a...
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... signaling pathways and molecular players are implicated in regulating the process of cilia disassembly (Figure 2). Based on the current literature, the molecular events regulating the process of cilia disassembly can be broadly categorized into (1) activation of AurA kinase and deacetylation of microtubules, (2) depolymerization of microtubules, and (3) ciliary membrane remodeling and inhibition of cilia assembly. ...
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Primary cilia are conserved organelles that integrate extracellular cues into intracellular signals and are critical for diverse processes, including cellular development and repair responses. Deficits in ciliary function cause multisystemic human diseases known as ciliopathies. In the eye, atrophy of the retinal pigment epithelium (RPE) is a commo...
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... We found that Chlamydia infection caused loss of the primary cilium by activating the cellular Introduction involves the mitotic kinase Aurora A, whose activation at the basal body requires Ca 2+ /calmodulin [24]. Activated Aurora phosphorylates its effector HDAC6 [22], which promotes cilia disassembly by deacetylating and destabilizing axonemal microtubules and by deacetylating cortactin to reorganize the actin cytoskeleton [21,22,25]. ...
... Similarly, C. trachomatis caused primary cilia loss in HeLa cells and three murine cell lines (IMCD3, NIH 3T3 cells and mouse embryonic fibroblasts (MEFs, S1A Fig). RPE-1 cells are diploid, non-transformed cells that are commonly used for primary cilia studies [21,22]. As RPE-1 cells readily form primary cilia when growth arrested through serum starvation, we used them for the rest of our cilia studies. ...
Chlamydia trachomatis is a clinically important bacterium that infects epithelial cells of the genitourinary and respiratory tracts and the eye. These differentiated cells are in a quiescent growth state and have a surface organelle called a primary cilium, but the standard Chlamydia cell culture infection model uses cycling cells that lack primary cilia. To investigate if these differences are relevant, we performed infections with host cells that have a primary cilium. We found that C . trachomatis caused progressive loss of the primary cilium that was prevented by disrupting Aurora A (AurA), HDAC6 or calmodulin, which are components of the cellular cilia disassembly pathway. Stabilization of the primary cilium by targeting this pathway caused a large reduction in infectious progeny although there were no changes in chlamydial inclusion growth, chlamydial replication or the ultrastructural appearance of dividing and infectious forms (RBs and EBs, respectively). Thus, the presence of a primary cilium interfered with the production of infectious EBs at a late step in the developmental cycle. C . trachomatis infection also induced quiescent cells to re-enter the cell cycle, as detected by EdU incorporation in S-phase, and Chlamydia -induced cilia disassembly was necessary for cell cycle re-entry. This study therefore describes a novel host-pathogen interaction in which the primary cilium limits a productive Chlamydia infection, and the bacterium counteracts this host cell defense by activating the cellular cilia disassembly pathway.
... However, BMP4-treated NSCs have relatively longer primary cilia than bFGF/BMP4-treated NSCs, which is an important morphological marker for distinguishing these cells. The extension of cilium is happened in G1/G0 of cell cycle, and the disassembling of extended cilium means that cells enter into other cell cycle phase (Paridaen et al., 2013;Malicki and Johnson, 2017), so the length of the primary cilia is negatively correlated with cell cycle progression (Li et al., 2011;Wilson et al., 2012;Patel and Tsiokas, 2021). Therefore, compared to bFGF/BMP4treated NSCs, the longer cilium of BMP4-treated NSCs correspond to the deeper state of quiescence. ...
Bone morphogenetic protein-4 (BMP4) is involved in regulation of neural stem cells (NSCs) proliferation, differentiation, migration and survival. It was previously thought that the treatment of NSCs with BMP4 alone induces astrocytes, whereas the treatment of NSCs with the bFGF/BMP4 combination induces quiescent neural stem cells (qNSCs). In this study, we performed bulk RNA sequencing (RNA-Seq) to compare the transcriptome profiles of BMP4-treated NSCs and bFGF/BMP4-treated NSCs, and found that both NSCs treated by these two methods were Sox2 positive qNSCs which were able to generate neurospheres. However, NSCs treated by those two methods exhibited different characteristics in state and the potential for neuronal differentiation based on transcriptome analysis and experimental results. We found that BMP4-treated NSCs tended to be in a deeper quiescent state than bFGF/BMP4-treated NSCs as the percentage of ki67-positive cells were lower in BMP4-treated NSCs. And after exposure to differentiated environment, bFGF/BMP4-treated NSCs generated more DCX-positive immature neurons and MAP2-positive neurons than BMP4-treated NSCs. Our study characterized qNSCs treated with BMP4 alone and bFGF/BMP4 combination, providing a reference for the scientific use of BMP4 and bFGF/BMP4-induced qNSCs models.
... Considering that AURKA plays a key role in ciliary disassembly, and GBM cells constantly assemble and disassemble their cilia while proliferating, it was surprising to not observe increased GBM cilia frequency after Alisertib treatment. It is possible that AURKA inhibition in GBM cells stimulates activity of other molecules that promote ciliary disassembly such as HDAC6, NEK and others (for review see: [22,36,37]). However, we previously reported that overexpression of HDAC6 in our L0 or S7 glioma cells did not reduce cilia frequency or length [33]. ...
Tumor Treating Fields (TTFields) extend the survival of glioblastoma (GBM) patients by interfering with a broad range of tumor cellular processes. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere with GBM ciliogenesis further suppress GBM cell proliferation in vitro. Aurora kinase A (AURKA) promotes both cilia disassembly and GBM growth. Inhibitors of AURKA, such as Alisertib, inhibit cilia disassembly and increase ciliary frequency in various cell types. However, we found that Alisertib treatment significantly reduced GBM cilia frequency in gliomaspheres across multiple patient derived cell lines, and in patient biopsies treated ex vivo. This effect appeared glioma cell-specific as it did not reduce normal neuronal or glial cilia frequencies. Alisertib-mediated depletion of glioma cilia appears specific to AURKA and not AURKB inhibition, and attributable in part to autophagy pathway activation. Treatment of two different GBM patient-derived cell lines with TTFields and Alisertib resulted in a significant reduction in cell proliferation compared to either treatment alone. However, this effect was not cilia-dependent as the combined treatment reduced proliferation in cilia-depleted cell lines lacking, ARL13B, or U87MG cells which are naturally devoid of ARL13B⁺ cilia. Thus, Alisertib-mediated effects on glioma cilia may be a useful biomarker of drug efficacy within tumor tissue. Considering Alisertib can cross the blood brain barrier and inhibit intracranial growth, our data warrant future studies to explore whether concomitant Alisertib and TTFields exposure prolongs survival of brain tumor-bearing animals in vivo.
... Considering that AURKA plays a key role in ciliary disassembly, and GBM cells constantly assemble and disassemble their cilia while proliferating, it was surprising to not observe increased GBM cilia frequency after Alisertib treatment. It is possible that AURKA inhibition in GBM cells stimulates activity of other molecules that promote ciliary disassembly such as HDAC6, NEK and others (for review see: (22,35,36)). However, we previously reported that overexpression of HDAC6 in our L0 or S7 glioma cells did not reduce cilia frequency or length (32). ...
Tumor Treating Fields (TTFields) have been shown to extend the survival of glioblastoma (GBM) patients. TTFields interfere with a broad range of cellular processes which may contribute to their efficacy. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere with GBM ciliogenesis can further suppress GBM cell proliferation in vitro. Aurora Kinase A (AURKA) promotes both cilia disassembly and GBM growth in vitro and in xenograft models. Inhibitors of AURKA such as Alisertib have been previously demonstrated to inhibit cilia disassembly and increase the frequency of cilia in various cell types. However, here we show that physiological concentrations of Alisertib treatment significantly reduced GBM cilia frequency in gliomaspheres across multiple patient derived cell lines, and in patient biopsies treated ex vivo with Alisertib. This activity of Alisertib seems to be glioma cell specific as it did not reduce neuronal or glial cilia frequencies in mixed primary cell cultures from mouse forebrain. Furthermore, Alisertib depletion of glioma cilia appears specific to AURKA inhibition, as a potent AURKB inhibitor, AZD1152, had no effect on GBM ciliary frequency. Treatment of two different GBM patient-derived cell lines with TTFields and Alisertib resulted in a significant reduction in cell proliferation compared to either treatment alone. However, this effect was not cilia-dependent as the combined treatment reduced proliferation in cilia-depleted cell lines lacking, ARL13b, or U87MG cells which are naturally devoid of ARL13B+ cilia. This result is not surprising given the wide range of pathways regulated by AURKA in addition to cilia. Nonetheless, Alisertib-mediated effects on glioma cilia may be a useful biomarker of drug efficacy within tumor tissue. Considering Alisertib has been shown to cross the blood brain barrier and inhibit intracranial growth of xenografted tumor models, our data warrant future studies to explore whether concomitant Alisertib and TTFields exposure prolongs survival of brain tumor-bearing animals in vivo.
... Dysregulated ciliary dynamics have been associated with several pathological conditions, including microcephaly and cancer Yeh et al, 2013;Gabriel et al, 2016;Chen et al, 2019;Zhang et al, 2019;Farooq et al, 2020;Shiromizu et al, 2020). Although the mechanism underlying the assembly has been extensively investigated, the mechanism and cellular machinery that underlies ciliary resorption are less well understood Saito et al, 2017;Wang & Dynlacht, 2018;Patel & Tsiokas, 2021). Ciliary dynamics have been widely studied in several non-transformed cell lines, including human retinal pigment epithelial cells (RPE-1), mouse embryonic fibroblasts, and NIH3T3 cells (Saito et al, 2018). ...
... The existing model suggests three main steps involved in the process of ciliary resorption: (1) the disassembly of the ciliary axonemal microtubule, (2) the prevention of the ciliary (re)assembly, and (3) the elimination of the extra ciliary luminal/ membrane components resulting from the axonemal disassembly (Liang et al, 2016;Hsu et al, 2017;Patel & Tsiokas, 2021). Emerging evidence (Clement et al, 2013;Saito et al, 2017) and the present study suggest that periciliary membrane endocytosis actively participates in ciliary resorption, rather than simply removing the unnecessary ciliary membrane components generated during cilium resorption. ...
The primary cilium undergoes cell cycle–dependent assembly and disassembly. Dysregulated ciliary dynamics are associated with several pathological conditions called ciliopathies. Previous studies showed that the localization of phosphorylated Tctex-1 at Thr94 (T94) at the ciliary base critically regulates ciliary resorption by accelerating actin remodeling and ciliary pocket membrane endocytosis. Here, we show that microtubule-associated serine/threonine kinase family member 4 (MAST4) is localized at the primary cilium. Suppressing MAST4 blocks serum-induced ciliary resorption, and overexpressing MAST4 accelerates ciliary resorption. Tctex-1 binds to the kinase domain of MAST4, in which the R503 and D504 residues are key to MAST4-mediated ciliary resorption. The ciliary resorption and the ciliary base localization of phospho-(T94)Tctex-1 are blocked by the knockdown of MAST4 or the expression of the catalytic-inactive site-directed MAST4 mutants. Moreover, MAST4 is required for Cdc42 activation and Rab5-mediated periciliary membrane endocytosis during ciliary resorption. These results support that MAST4 is a novel kinase that regulates ciliary resorption by modulating the ciliary base localization of phospho-(T94)Tctex-1. MAST4 is a potential new target for treating ciliopathies causally by ciliary resorption defects.
... 34 Moreover, planar polarity mechanisms make sure the orientation of all EPCs' apical and basal domains is in the same direction, and the normal intercellular communication, which coordinated beatings of multiple motile cilia with synchronized orientation, generates directional fluid flow on the tissue surface. 35 The pioneering study revealed that the anatomical and functional integrity of the CC is intimately linked to the integrity of the cytoskeleton of the multiple cells lining its lumen, 36 which is therefore closely related to the maintenance of normal CSF circulation and the balance of parenchymal microenvironment by coordinating the cilia oscillations. 37 According to our results, during the CC expansion, abnormal cell polarity was seen in the ependymal region as well as loss of motile cilia and disruption of tight or gap junction. ...
Syringomyelia is a common clinical lesion associated with cerebrospinal fluid flow abnormalities. By a reversible model with chronic extradural compression to mimic human canalicular syringomyelia, we explored the spatiotemporal pathological alterations during syrinx development. The most dynamic alterations were observed in ependymal cells (EPCs), oligodendrocyte lineage, and microglia, as a response to neuroinflammation. Among different cell types, EPC subtypes experienced obvious dynamic alterations, which were accompanied by ultrastructural changes involving the ependymal cytoskeleton, cilia, and dynamic injury in parenchyma primarily around the central canal, corresponding to the single-cell transcripts. After effective decompression, the syrinx resolved with the recovery of pathological damage and overall neurological function, implying that for syringomyelia in the early stage, there was still endogenous repair potential coexisting with immune microenvironment imbalance. Ependymal remodeling and cilia restoration might be important for better resolution of syringomyelia and parenchymal injury recovery.
... This creates a protrusion, which ultimately becomes a cilium. As the cell reenters the cell cycle, the cilium will disassemble either through shedding or through axonemal disassembly before entering cell division (Patel & Tsiokas, 2021). ...
MAPK pathways are well-known regulators of the cell cycle, but they have also been found to control ciliary length in a wide variety of organisms and cell types from Caenorhabditis elegans neurons to mammalian photoreceptors through unknown mechanisms. ERK1/2 is a MAP kinase in human cells that is predominantly phosphorylated by MEK1/2 and dephosphorylated by the phosphatase DUSP6. We have found that the ERK1/2 activator/DUSP6 inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI), inhibits ciliary maintenance in Chlamydomonas and hTERT-RPE1 cells and assembly in Chlamydomonas . These effects involve inhibition of total protein synthesis, microtubule organization, membrane trafficking, and KAP-GFP motor dynamics. Our data provide evidence for various avenues for BCI-induced ciliary shortening and impaired ciliogenesis that gives mechanistic insight into how MAP kinases can regulate ciliary length.
... 24 Defective Rhodopsin trafficking is considered a common feature of RD in multiple ciliopathy models; moreover, in BBS animal models, endoplasmic reticulum stress response has been described. 25 Obesity BBS patients commonly manifest with obesity, in 72-92% of cases. Patients typically show normal body weight at birth, but in 90% of cases they gain weight in the first year of life and obesity becomes evident during the first 3 years of life. ...
The Bardet Biedl syndrome (BBS) is a rare inherited disorder considered a model of non-motile ciliopathy. It is in fact caused by mutations of genes encoding for proteins mainly localized to the base of the cilium. Clinical features of BBS patients are widely shared with patients suffering from other ciliopathies, especially autosomal recessive syndromic disorders; moreover, mutations in cilia-related genes can cause different clinical ciliopathy entities. Besides the best-known clinical features, as retinal degeneration, learning disabilities, polydactyly, obesity and renal defects, several additional clinical signs have been reported in BBS, expanding our understanding of the complexity of its clinical spectrum. The present review aims to describe the current knowledge of BBS i) pathophysiology, ii) clinical manifestations, highlighting both the most common and the less described features, iii) current and future perspective for treatment.
... The assembly and disassembly of cilia is dynamic during developmental processes, which include cell proliferation and cell differentiation (Patel & Tsiokas, 2021). Several cilia assembly and disassembly factors and pathways have been described (Hossain & Tsang, 2019;Lee, 2020;Sánchez & Dynlacht, 2016). ...
Cilia are hair‐like structures that project from the surface of cells. In vertebrates, most cells have an immotile primary cilium that mediates cell signaling, and some specialized cells assemble one or multiple cilia that are motile and beat synchronously to move fluids in one direction. Gene mutations that alter cilia structure or function cause a broad spectrum of disorders termed ciliopathies that impact virtually every system in the body. A wide range of birth defects associated with ciliopathies underscores critical functions for cilia during embryonic development. In many cases, the mechanisms underlying cilia functions during development and disease remain poorly understood. This review describes different types of cilia in vertebrate embryos and discusses recent research results from diverse model systems that provide novel insights into how cilia form and function during embryo development. The work discussed here not only expands our understanding of in vivo cilia biology, but also opens new questions about cilia and their roles in establishing healthy embryos.
Dermestes frischii Kugelann, 1792 is a storage pest worldwide, and is important for estimating the postmortem interval in forensic entomology. However, because of the lack of transcriptome and genome resources, population genetics and biological control studies on D. frischii have been hindered. Here, single-molecule real-time sequencing and next-generation sequencing were combined to generate the full-length transcriptome of the five developmental stages of D. frischii , namely egg, young larva, mature larva, pupa, and adult. A total of 41665 full-length non-chimeric sequences and 59385 non-redundant transcripts were generated, of which 42756 were annotated in public databases. By comparing the transcripts from adjacent developmental stages, 24376, 11802, 20726, and 13262 differentially expressed genes were identified, respectively. Using the weighted gene co-expression network analysis, gene co-expression modules related to the five developmental stages were constructed and screened, and the genes in these modules subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The expression patterns of the DEGs related to olfaction and insect hormone biosynthesis were also explored. Transcription of most odorant binding proteins was up-regulated in the adult stage, suggesting they are important for foraging in adults. Many genes encoding for the ecdysone-inducible protein were up-regulated in the pupal stage. The results of the qRT-PCR were consistent with the RNA-seq results. This is the first full-length transcriptome sequencing of dermestids, and the data obtained here is vital for understanding the stage-specific development and olfactory system of D. frischii , providing valuable resources for storage pest and forensic research.
