Figure 4 - available via license: Creative Commons Attribution 2.0 Generic
Content may be subject to copyright.
Cilia length in control of cell cycle progression. Cilia provide a physical block for cell cycle progression by laying claim to the basal body. Disassembly of the primary cilium is required to liberate the centrosome and allow duplication during S-phase and subsequent formation of the mitotic spindle during chromosomal segregation. Cilia mutants that inhibit ciliogenesis are prone to initiate rapid cell duplication when properly stimulated, and in contrast, increased axonemal length delays cell cycle progression. The maturation steps (growth and appendages) of the centrioles are indicated during the various cell cycle stages.
Source publication
Dysfunctional cilia underlie a broad range of cellular and tissue phenotypes and can eventually result in the development of ciliopathies: pathologically diverse diseases that range from clinically mild to highly complex and severe multi-organ failure syndromes incompatible with neonatal life. Given that virtually all cells of the human body have t...
Similar publications
Joubert syndrome (JS) is a congenital autosomal-recessive or—in rare cases–X-linked inherited disease. The diagnostic hallmark of the so-called molar tooth sign describes the morphological manifestation of the mid- and hind-brain in axial brain scans. Affected individuals show delayed development, intellectual disability, ataxia, hyperpnea, sleep a...
New generation technologies in cell and molecular biology generate large amounts of data hard to exploit for individual proteins. This is particularly true for ciliary and centrosomal research. Cildb is a multi-species knowledgebase gathering high throughput studies, which allows advanced searches to identify proteins involved in centrosome, basal...
Citations
... The primary cilium may mediate its anti-chlamydial effect through several potential mechanisms. It could be exerted through the known function of the primary cilium as a transduction hub for multiple signaling pathways, including Hedgehog, PDGF, Wnt and Notch signaling [34]. Alternatively, it could be related to autophagy, which is regulated by the primary cilium [35] and has been shown to restrict C. trachomatis growth [36]. ...
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.
... This pathway is essential not only for embryonic development and organogenesis but also for the maintenance and repair of adult tissue homeostasis . Anomalous activation of the Hh pathway is pivotal for the pathogenesis of various cancers, encompassing medulloblastoma, basal cell carcinoma, breast cancer, prostate cancer, melanoma, lung cancer, and pancreatic cancer (Ross et al., 2005;Luu et al., 2009;Seeley et al., 2009;Yuan et al., 2010;Kim et al., 2011;Basten and Giles, 2013;Gradilone et al., 2013;Hassounah et al., 2013;Wang, 2021;Giammona et al., 2023). In mammals, Hh signal transduction is orchestrated through primary cilia located on cells . ...
Primary cilia, serving as the central hub for cellular signal transduction, possess the remarkable ability to translate diverse extracellular signals, both chemical and mechanical, into intracellular responses. Their ubiquitous presence in the reproductive system underscores their pivotal roles in various cellular processes including development, differentiation, and migration. Emerging evidence suggests primary cilia as key players in reproductive physiology and associated pathologies. Notably, primary cilia have been identified in granulosa cells within mouse ovaries and uterine stromal cells, and perturbations in their structure and function have been implicated in a spectrum of reproductive dysfunctions and ciliary-related diseases. Furthermore, disruptions in primary cilia-mediated signal transduction pathways under pathological conditions exacerbate the onset and progression of reproductive disorders. This review provides a comprehensive overview of current research progress on primary cilia and their associated signaling pathways in reproductive physiology and diseases, with the aim of furnishing theoretical groundwork for the prevention and management of primary cilia-related structural and functional abnormalities contributing to reproductive system pathologies.
... Various cancer cells have been shown to lack cilia expression (Menzl et al., 2014;Cao and Zhong, 2016;Higgins et al., 2019). Changes in primary cilia have been noted in renal, prostate, cholangiocarcinoma, pancreatic, skin, brain and breast cancers (Seeley et al., 2009;Basten and Giles, 2013;Hassounah et al., 2013;Seeger-Nukpezah et al., 2013;Menzl et al., 2014;Snedecor et al., 2015;Higgins et al., 2019). Renal epithelial and human primary melanoma cells demonstrate significant losses of cilia in response to carcinogens Snedecor et al., 2015;Higgins et al., 2019). ...
Cilia are cellular signaling hubs. Given that human kinases are central regulators of signaling, it is not surprising that kinases are key players in cilia biology. In fact, many kinases modulate ciliogenesis, which is the generation of cilia, and distinct ciliary pathways. Several of these kinases are understudied with few publications dedicated to the interrogation of their function. Recent efforts to develop chemical probes for members of the cyclin-dependent kinase like (CDKL), never in mitosis gene A (NIMA) related kinase (NEK), and tau tubulin kinase (TTBK) families either have delivered or are working toward delivery of high-quality chemical tools to characterize the roles that specific kinases play in ciliary processes. A better understanding of ciliary kinases may shed light on whether modulation of these targets will slow or halt disease onset or progression. For example, both understudied human kinases and some that are more well-studied play important ciliary roles in neurons and have been implicated in neurodevelopmental, neurodegenerative, and other neurological diseases. Similarly, subsets of human ciliary kinases are associated with cancer and oncological pathways. Finally, a group of genetic disorders characterized by defects in cilia called ciliopathies have associated gene mutations that impact kinase activity and function. This review highlights both progress related to the understanding of ciliary kinases as well as in chemical inhibitor development for a subset of these kinases. We emphasize known roles of ciliary kinases in diseases of the brain and malignancies and focus on a subset of poorly characterized kinases that regulate ciliary biology.
... Primary cilia play a significant role in regulating cell behavior, particularly in influencing cell cycle progression and suppressing proliferative signaling. [35][36][37] The disassembly of primary cilia facilitates cell proliferation, and their absence is linked to excessive cell proliferation observed in conditions like cancer. 35,36 Signaling pathways like Shh and Notch, known regulators of cell proliferation and differentiation across various tissues and cell types, are influenced by primary cilia. ...
... [35][36][37] The disassembly of primary cilia facilitates cell proliferation, and their absence is linked to excessive cell proliferation observed in conditions like cancer. 35,36 Signaling pathways like Shh and Notch, known regulators of cell proliferation and differentiation across various tissues and cell types, are influenced by primary cilia. 23,38,39 Deletion of Ift88 or Kif3a in different contexts results in hyperproliferation in the epidermis or myoblasts. ...
Purpose:
Intraflagellar transport 46 (IFT46) is an integral subunit of the IFT-B complex, playing a key role in the assembly and maintenance of primary cilia responsible for transducing signaling pathways. Despite its predominant expression in the basal body of cilia, the precise role of Ift46 in ocular development remains undetermined. This study aimed to elucidate the impact of neural crest (NC)-specific deletion of Ift46 on ocular development.
Methods:
NC-specific conditional knockout mice for Ift46 (NC-Ift46F/F) were generated by crossing Ift46F mice with Wnt1-Cre2 mice, enabling the specific deletion of Ift46 in NC-derived cells (NCCs). Sonic Hedgehog (Shh) and Notch signaling activities in NC-Ift46F/F mice were evaluated using Gli1lacZ and CBF:H2B-Venus reporter mice, respectively. Cell fate mapping was conducted using ROSAmTmG reporter mice.
Results:
The deletion of Ift46 in NCCs resulted in a spectrum of ocular abnormalities, including thickened corneal stroma, hypoplasia of the anterior chamber, irregular iris morphology, and corneal neovascularization. Notably, this deletion led to reduced Shh signal activity in the periocular mesenchyme, sustained expression of key transcription factors Foxc1, Foxc2 and Pitx2, along with persistent cell proliferation. Additionally, it induced increased Notch signaling activity and the development of ectopic neovascularization within the corneal stroma.
Conclusions:
The absence of primary cilia due to Ift46 deficiency in NCCs is associated with anterior segment dysgenesis (ASD) and corneal neovascularization, suggesting a potential link to Axenfeld-Rieger syndrome, a disorder characterized by ASD. This underscores the pivotal role of primary cilia in ensuring proper anterior segment development and maintaining an avascular cornea.
... Although this is not completely deterministic, mutations in genes encoding ciliary TZ proteins often lead to neurodevelopmental ciliopathies such as Joubert Syndrome (JS) and the embryonically lethal Meckel Gruber syndrome (MKS) (1,3). It was demonstrated that primary cilia are present throughout the neuronal lineage, from neural stem to progenitor cells, mature neurons and glia, where they play an essential role in CNS formation by modulating signaling pathways and cell cycle progression (4)(5)(6)(7)(8)(9)(10). ...
Studying developmental processes in the context of the human central nervous system is essential to understand neurodevelopmental diseases. In this paper we perform a comparative functional study of the ciliopathy gene RPGRIP1L in human and mouse spinal development using in vitro 3D differentiation of pluripotent stem cells. RGPRIP1L, a causal gene of severe neurodevelopmental ciliopathies such as Joubert and Meckel syndromes, encodes a scaffolding protein of the ciliary transition zone involved in ciliary gating. Previous work has identified a major role for Rpgrip1l in mouse brain and spinal cord development, via controlling the Sonic Hedgehog (SHH)/GLI pathway. We show that spinal organoids derived from Rpgrip1l mutant mouse embryonic stem cells faithfully recapitulate the loss of motoneurons and the strong reduction of SHH signaling observed in the mutant mice. In contrast, human induced pluripotent stem cells mutant for RPGRIP1L produce motoneurons and activate the SHH pathway at levels similar to wild types. Moreover, we show that, in human RPGRIP1L mutant organoids, MNs acquire a more anterior identity, expressing HOX genes and proteins normally present in the hindbrain while motoneurons from wild type organoids strictly display spinal identity. By performing a temporal transcriptome analysis throughout the differentiation process, we find that the anteroposterior specification defect arises in early axial progenitors. Thus, this study uncovers distinct functions in humans and mice for a ciliopathy protein and a novel role for RPGRIP1L in human spinal anteroposterior patterning. These findings have important implications for understanding the role of cilia in human spinal cord development and the pathogenic mechanisms of neurodevelopmental ciliopathies.
... Since microtubules are a critical component of primary cilia, primary cilia regulate cell cycle processes. They can prevent abnormal cell growth by restricting the cell cycle in studies of the CRP effect on the primary cilia of OPCs [2,12]. The present study showed more primary cilia on recombinant CRP-treated OPCs than on control OPCs, indicating that CRP abnormally activated primary cilia formation (Fig. 3C-E). ...
Inflammation disrupts bone metabolism and leads to bone damage. C-reactive protein (CRP) is a typical inflammation marker. Although CRP measurement has been conducted for many decades, how osteoblastic differentiation influences molecular mechanisms remains largely unknown. The present study attempted to investigate the effects of CRP on primary cultured osteoblast precursor cells (OPCs) while elucidating the underlying molecular mechanisms. OPCs were isolated from suckling Sprague-Dawleyrats. Fewer OPCs were observed after recombinant C-reactive protein treatment. In a series of experiments, CRP inhibited OPC proliferation, osteoblastic differentiation, and the OPC gene expression of the hedgehog (Hh) signaling pathway. The inhibitory effect of CRP on OPC proliferation occurred via blockade of the G1-S transition of the cell cycle. In addition, the regulation effect of proto cilium on osteoblastic differentiation was analyzed using the bioinformatics p. This revealed the primary cilia activation of recombinant CRP effect on OPCs through in vitro experiments. A specific Sonic Hedgehog signaling agonist (SAG) rescued osteoblastic differentiation inhibited by recombinant CRP. Moreover, chloral hydrate, which removes primary cilia, inhibited the Suppressor of Fused (SUFU) formation and blocked Gli2 degradation. This counteracted osteogenesis inhibition caused by CRP. Therefore, these data depict that CRP can inhibit the proliferation and osteoblastic differentiation of OPCs. The underlying mechanism could be associated with primary cilia activation and Hh pathway repression.
... Ciliogenesis in cancer cells is dependent on the cancer type. Unsurprisingly, most cancer cells lack cilia because they serve as gatekeepers to stop cell cycle re-entry [116][117][118]. Nevertheless, several others exhibit increased numbers of primary cilia [119]. ...
Cancer whose major problems are metastasis, treatment resistance, and recurrence is the leading cause of death worldwide. Tumor-initiating stem cells (TiSCs) are a subset of the tumor population responsible for tumor resistance and relapse. Understanding the characteristics and shared features between tumor-initiating stem cells (TiSCs) and long-lived postmitotic cells may hold a key to better understanding the biology of cancer. Postmitotic cells have exited the cell cycle and are transitioned into a non-dividing and terminally differentiated state with a specialized function within a tissue. Conversely, a cancer cell with TiSC feature can divide and produce a variety of progenies, and is responsible for disease progression, tumor resistance to therapy and immune system and disease relapse. Surprisingly, our comprehensive evaluation of TiSCs suggests common features with long-lived post-mitotic cells. They are similar in structure (primary cilia, high mitochondrial content, and being protected by a barrier), metabolism (autophagy and senescence), and function (immunoescape and/or immune-privileged by a blood barrier). In-depth exploration showed how mitochondrial metabolism contributes to these shared features, including high energy demands arising from ciliary and microtubular functionality, increased metabolic activity, and movement. These findings can assist in decoding the remaining properties which offer insights into the biology of TiSCs, with potential implications for enhancing cancer treatment strategies and patient prognosis. Keywords: blood barrier; cilium; immunity; postmitotic cells; tumor-initiating stem cells; tumor microenvironment
... We previously revealed that maternal protein deficiency led to upregulation of the ciliogenesis factors IFT88 and PKD in FGR offspring (14). Downregulation of IFT88 was reported to activate Wnt pathway and promote β-catenin nuclear translocation (15). Cilia dysfunction caused by Pkd1 deletion also causes renal Wnt7a/7b overexpression and activates Wnt/β-catenin pathway (16). ...
... Primary cilia modulate tubular epithelial cell maturation during embryonic stage by regulating Wnt signaling pathways (36,37), for various Wnt pathway proteins, including degradation complexes and calmodulin regulator planar cell polarity (PCP) protein, are localized to the cilia or the basal body. IFT88 knockdown leads to a decrease in β-catenin phosphorylation and promotes nuclear translocation of β-catenin (15). Dysfunction of cilia caused by PKD2 knockout in mice leads to overexpression of Wnt7a/7b and activation of the Wnt/βcatenin pathway in the kidneys (10). ...
Introduction
Intrauterine malnutrition impairs embryo kidney development and leads to kidney disease and hypertension in adulthood, yet the underlying mechanism remains unclear.
Methods
With a maternal protein restriction (MPR) rat model, we investigated the critical ciliogenesis factors and β-catenin pathway in FGR fetal kidneys and analyzed the impact of aberrant primary cilia on renal tubular epithelium.
Results
The data showed decreased nephron number and renal tubular dysgenesis in FGR fetus. FGR fetus showed deregulated expression of ciliogenesis factors including upregulation of IFT88 and downregulation of DYNLT1, accompanied with cilia elongation in renal tubular epithelial cells. Wnt7b, the key ligand for Wnt/β-catenin signaling, was downregulated and nuclear translocation of β-catenin was decreased. The proapoptotic protein was upregulated. In vitro study with HK-2 cells showed that overexpression of IFT88 lengthened the cilia, inhibited β-catenin signaling. Besides, IFT88 overexpression suppressed cell proliferation, activated autophagy, and induced cell apoptosis. Inhibition of autophagy partly restored the cilia length and cell viability. Likewise, knockdown of DYNLT1 led to cilia elongation, suppressed cell proliferation, and promoted apoptosis in HK-2 cell. However, the cilia elongation induced by DYNLT1 knockdown was not autophagy-dependent, but associated with reactive oxygen species (ROS) accumulation.
Discussion
We elucidated that intrauterine protein malnutrition led to deregulation of ciliogenesis factors and cilia elongation in renal tubular epithelial, inhibited β-catenin signaling, and induced cell apoptosis and ultimately, compromised kidney development.
... This particular composition is maintained through a specialized region at the proximal end named the transition zone, which acts as a selective barrier of cilium (Park and Leroux 2022;Wang et al. 2022). The primary cilium is widely considered an antenna of the cell, acting as a central hub for coordinating multiple most of cellular signaling pathways (Basten and Giles 2013). ...
Purpose:
Glioma is a highly malignant and unfavorable cancer in the brain. Recent evidence highlights the vital role of cilia-related pathways as novel regulators of glioma development. However, the prognostic potential of ciliary pathways in glioma is still ambiguous. In this study, we aim to construct a gene signature using cilia-related genes to facilitate the prognostication of glioma.
Methods:
A multi-stage approach was employed to build the ciliary gene signature for prognostication of glioma. The strategy involved the implementation of univariate, LASSO, and stepwise multivariate Cox regression analyses based on TCGA cohort, followed by independent validation in CGGA and REMBRANDT cohort. The study further revealed molecular differences at the genomic, transcriptomic, and proteomic levels between distinct groups.
Results:
A prognostic tool utilizing a 9-gene signature based on ciliary pathways was developed to assess the clinical outcomes of glioma patients. The risk scores generated by the signature demonstrated a negative correlation with patient survival rates. The validation of the signature in an independent cohort reinforced its prognostic capabilities. In-depth analysis uncovered distinctive molecular characteristics at the genomic, transcriptomic, and protein-interactive levels in the high- and low-risk groups. Furthermore, the gene signature was able to predict the sensitivity of glioma patients to conventional chemotherapeutic drugs.
Conclusion:
This study has established the utility of a ciliary gene signature as a reliable prognostic predictor of glioma patient survival. Findings not only enhance our comprehension of the intricate molecular mechanisms of cilia pathways in glioma, but also hold significant clinical implications in directing chemotherapeutic strategies.
... 2 Primary cilia-related signal transduction in the context of tumorigenesis Primary cilia mediate cancer-related signaling such as the Sonic hedgehog, Wingless/INT (Wnt), NOTCH, platelet-derived growth factor (PDGF), mammalian target of rapamycin (mTOR), and Hippo pathways (Basten and Giles, 2013;Liu et al., 2018;Fabbri et al., 2019). Here, we focus on two major cilia-related cancer signal pathways. ...
... When the SHH ligand binds to the PTCH1 receptor, which is the 12-transmembrane patched 1 protein localized on the ciliary membrane in the absence of SHH ligand, it translocates to the outside of the cilia. Following the ciliary exit of PTCH1, the seventransmembrane protein smoothened (SMO) enters the ciliary membrane to induce the release of GLI transcriptional protein known as glioma-associated oncogene from the Suppressor of fused (SUFU) protein in the ciliary cytoplasm, thereby shuttling GLI from the primary cilium compartment to the nucleus to control the transcription of GLI-target genes (Figure 2; Basten and Giles, 2013;Byrne et al., 2016;Qi et al., 2018;Liu et al., 2018;Fabbri et al., 2019;Niewiadomski et al., 2019). Germline mutations of the PTCH1 gene causes autosomal-dominant Gorlin syndrome with basal cell ...
Primary cilium is a non-motile, antenna-like structure that develops in the quiescent G 0 phase-cell surface. It is composed of an array of axonemal microtubules polymerized from the centrosome/basal body. The plasma membrane surrounding the primary cilium, which is called the ciliary membrane, contains a variety of receptors and ion channels, through which the cell receives extracellular chemical and physical stimuli to initiate signal transduction. In general, primary cilia disappear when cells receive the proliferative signals to re-enter the cell cycle. Primary cilia thus cannot be identified in many malignant and proliferative tumors. In contrast, some cancers, including basal cell carcinoma, medulloblastoma, gastrointestinal stromal tumor, and other malignancies, retain their primary cilia. Importantly, it has been reported that the primary cilia-mediated oncogenic signals of Hedgehog, Wnt, and Aurora kinase A are involved in the tumorigenesis and tumor progression of basal cell carcinoma and some types of medulloblastoma. It has also been demonstrated that cholesterol is significantly more enriched in the ciliary membrane than in the rest of the plasma membrane to ensure Sonic hedgehog signaling. A series of epidemiological studies on statin drugs (cholesterol-lowering medication) demonstrated that they prevent recurrence in a wide range of cancers. Taken together, ciliary cholesterol could be a potential therapeutic target in primary cilia-dependent progressive cancers.
