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Keywords: cilia
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Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2021) 49 (1): 79–91.
Published: 18 February 2021
...Pablo Barbeito; Francesc R. Garcia-Gonzalo Primary cilia are hair-like projections of the cell membrane supported by an inner microtubule scaffold, the axoneme, which polymerizes out of a membrane-docked centriole at the ciliary base. By working as specialized signaling compartments, primary cilia...
Abstract
Primary cilia are hair-like projections of the cell membrane supported by an inner microtubule scaffold, the axoneme, which polymerizes out of a membrane-docked centriole at the ciliary base. By working as specialized signaling compartments, primary cilia provide an optimal environment for many G protein-coupled receptors (GPCRs) and their effectors to efficiently transmit their signals to the rest of the cell. For this to occur, however, all necessary receptors and signal transducers must first accumulate at the ciliary membrane. Serotonin receptor 6 (HTR6) and Somatostatin receptor 3 (SSTR3) are two GPCRs whose signaling in brain neuronal cilia affects cognition and is implicated in psychiatric, neurodegenerative, and oncologic diseases. Over a decade ago, the third intracellular loops (IC3s) of HTR6 and SSTR3 were shown to contain ciliary localization sequences (CLSs) that, when grafted onto non-ciliary GPCRs, could drive their ciliary accumulation. Nevertheless, these CLSs were dispensable for ciliary targeting of HTR6 and SSTR3, suggesting the presence of additional CLSs, which we have recently identified in their C-terminal tails. Herein, we review the discovery and mapping of these CLSs, as well as the state of the art regarding how these CLSs may orchestrate ciliary accumulation of these GPCRs by controlling when and where they interact with the ciliary entry and exit machinery via adaptors such as TULP3, RABL2 and the BBSome.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2021) 49 (1): 467–476.
Published: 05 February 2021
... (CC BY) . cancer stem cells centrosomes cilia KRAS trafficking During the morphogenesis of normal tissues, the balance between stem cell self-renewal and differentiation is regulated by symmetric and asymmetric cell divisions [ 1 ]. Certain features of these ontogenetic processes are...
Abstract
Cancer stem cells (CSC) may be the most relevant and elusive cancer cell population, as they have the exquisite ability to seed new tumors. It is plausible, that highly mutated cancer genes, such as KRAS , are functionally associated with processes contributing to the emergence of stemness traits. In this review, we will summarize the evidence for a stemness driving activity of oncogenic Ras. This activity appears to differ by Ras isoform, with the highly mutated KRAS having a particularly profound impact. Next to established stemness pathways such as Wnt and Hedgehog (Hh), the precise, cell cycle dependent orchestration of the MAPK-pathway appears to relay Ras activation in this context. We will examine how non-canonical activities of K-Ras4B (hereafter K-Ras) could be enabled by its trafficking chaperones calmodulin and PDE6D/PDEδ. Both dynamically localize to the cellular machinery that is intimately linked to cell fate decisions, such as the primary cilium and the centrosome. Thus, it can be speculated that oncogenic K-Ras disrupts fundamental polarized signaling and asymmetric apportioning processes that are necessary during cell differentiation.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2020) 48 (5): 2347–2357.
Published: 20 October 2020
... ) 12 8 2020 21 9 2020 22 9 2020 © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society 2020 asthma chronic obstructive pulmonary disease cilia cystic fibrosis mucus Xenopus Figure 1. Comparison of human large airway...
Abstract
Xenopus tadpoles have emerged as a powerful in vivo model system to study mucociliary epithelia such as those found in the human airways. The tadpole skin has mucin-secreting cells, motile multi-ciliated cells, ionocytes (control local ionic homeostasis) and basal stem cells. This cellular architecture is very similar to the large airways of the human lungs and represents an easily accessible and experimentally tractable model system to explore the molecular details of mucociliary epithelia. Each of the cell types in the tadpole skin has a human equivalent and a conserved network of genes and signalling pathways for their differentiation has been discovered. Great insight into the function of each of the cell types has been achieved using the Xenopus model and this has enhanced our understanding of airway disease. This simple model has already had a profound impact on the field but, as molecular technologies (e.g. gene editing and live imaging) continue to develop apace, its use for understanding individual cell types and their interactions will likely increase. For example, its small size and genetic tractability make it an ideal model for live imaging of a mucociliary surface especially during environmental challenges such as infection. Further potential exists for the mimicking of human genetic mutations that directly cause airway disease and for the pre-screening of drugs against novel therapeutic targets.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2020) 48 (5): 1929–1939.
Published: 08 September 2020
...Manuela Morleo; Brunella Franco The OFD1 gene was initially identified as the gene responsible for the X-linked dominant male lethal OFD type I syndrome, a developmental disorder ascribed to cilia disfunction. The transcript has been subsequently associated to four different X-linked recessive...
Abstract
The OFD1 gene was initially identified as the gene responsible for the X-linked dominant male lethal OFD type I syndrome, a developmental disorder ascribed to cilia disfunction. The transcript has been subsequently associated to four different X-linked recessive conditions, namely Joubert syndrome, retinitis pigmentosa, primary ciliary dyskinesia and Simpson–Golabi–Behmel type 2 syndrome. The centrosomal/basal body OFD1 protein has indeed been shown to be required for primary cilia formation and left–right asymmetry. The protein is also involved in other tasks, e.g. regulation of cellular protein content, constrain of the centriolar length, chromatin remodeling at DNA double strand breaks, control of protein quality balance and cell cycle progression, which might be mediated by non-ciliary activities. OFD1 represents a paradigmatic model of a protein that performs its diverse actions according to the cell needs and depending on the subcellular localization, the cell type/tissue and other possible factors still to be determined. An increased number of multitask protein, such as OFD1, may represent a partial explanation to human complexity, as compared with less complex organisms with an equal or slightly lower number of proteins.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2020) 48 (3): 1067–1075.
Published: 03 June 2020
...Jean-André Lapart; Amélie Billon; Jean-Luc Duteyrat; Joëlle Thomas; Bénédicte Durand Cilia play important signaling or motile functions in various organisms. In Human, cilia dysfunctions are responsible for a wide range of diseases, called ciliopathies. Cilia assembly is a tightly controlled...
Abstract
Cilia play important signaling or motile functions in various organisms. In Human, cilia dysfunctions are responsible for a wide range of diseases, called ciliopathies. Cilia assembly is a tightly controlled process, which starts with the conversion of the centriole into a basal body, leading to the formation of the ciliary bud that protrudes inside a ciliary vesicle and/or ultimately at the cell surface. Ciliary bud formation is associated with the assembly of the transition zone (TZ), a complex architecture of proteins of the ciliary base which plays critical functions in gating proteins in and out of the ciliary compartment. Many proteins are involved in the assembly of the TZ, which shows structural and functional variations in different cell types or organisms. In this review, we discuss how a particular complex, composed of members of the DZIP1, CBY and FAM92 families of proteins, is required for the initial stages of cilia assembly leading to ciliary bud formation and how their functional hierarchy contributes to TZ assembly. Moreover, we summarize how evidences in Drosophila reveal functional differences of the DZIP1–CBY–FAM92 complex in the different ciliated tissues of this organism. Whereas it is essential for proper TZ assembly in the two types of ciliated tissues, it is involved in stable anchoring of basal bodies to the plasma membrane in male germ cells. Overall, the DZIP1–CBY–FAM92 complex reveals a molecular assembly pathway required for the initial stages of ciliary bud formation and that is conserved from Drosophila to Human.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2020) 48 (1): 231–243.
Published: 25 February 2020
... signaling pathways to create the elaborately branched structure of the lung by controlling the directional protrusive movements of cells during branching morphogenesis. PCP operates in the airway epithelium to establish and maintain the orientation of respiratory cilia along the airway axis for anatomically...
Abstract
The planar cell polarity (PCP) signaling pathway is a potent developmental regulator of directional cell behaviors such as migration, asymmetric division and morphological polarization that are critical for shaping the body axis and the complex three-dimensional architecture of tissues and organs. PCP is considered a noncanonical Wnt pathway due to the involvement of Wnt ligands and Frizzled family receptors in the absence of the beta-catenin driven gene expression observed in the canonical Wnt cascade. At the heart of the PCP mechanism are protein complexes capable of generating molecular asymmetries within cells along a tissue-wide axis that are translated into polarized actin and microtubule cytoskeletal dynamics. PCP has emerged as an important regulator of developmental, homeostatic and disease processes in the respiratory system. It acts along other signaling pathways to create the elaborately branched structure of the lung by controlling the directional protrusive movements of cells during branching morphogenesis. PCP operates in the airway epithelium to establish and maintain the orientation of respiratory cilia along the airway axis for anatomically directed mucociliary clearance. It also regulates the establishment of the pulmonary vasculature. In adult tissues, PCP dysfunction has been linked to a variety of chronic lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, and idiopathic pulmonary arterial hypertension, stemming chiefly from the breakdown of proper tissue structure and function and aberrant cell migration during regenerative wound healing. A better understanding of these (impaired) PCP mechanisms is needed to fully harness the therapeutic opportunities of targeting PCP in chronic lung diseases.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2018) 46 (6): 1463–1473.
Published: 21 November 2018
... microtubules (specifically, the acetylated microtubular axoneme of the photoreceptor connecting cilium) and their role in normal photoreceptor function. This has been driven by the emerging field of ciliopathies, human diseases arising from mutations in genes required for cilia formation or function, of which...
Abstract
Retinitis pigmentosa (RP) is the leading cause of inherited blindness. RP is a genetically heterogeneous disorder, with more than 100 different causal genes identified in patients. Central to disease pathogenesis is the progressive loss of retinal photoreceptors. Photoreceptors are specialised sensory neurons that exhibit a complex and highly dynamic morphology. The highly polarised and elaborated architecture of photoreceptors requires precise regulation of numerous cytoskeletal elements. In recent years, significant work has been placed on investigating the role of microtubules (specifically, the acetylated microtubular axoneme of the photoreceptor connecting cilium) and their role in normal photoreceptor function. This has been driven by the emerging field of ciliopathies, human diseases arising from mutations in genes required for cilia formation or function, of which RP is a frequently reported phenotype. Recent studies have highlighted an intimate relationship between cilia and the actin cystoskeleton. This review will focus on the role of actin in photoreceptors, examining the connection between actin dysregulation in RP.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2018) 46 (4): 967–982.
Published: 31 July 2018
... along the axoneme of eukaryotic cilia and flagella. Both dyneins operate as large ATP-driven motor complexes, whose dysfunction is associated with a group of human disorders. But how similar are their mechanisms of action and regulation? To examine this question, this review focuses on recent advances...
Abstract
Two classes of dynein power long-distance cargo transport in different cellular contexts. Cytoplasmic dynein-1 is responsible for the majority of transport toward microtubule minus ends in the cell interior. Dynein-2, also known as intraflagellar transport dynein, moves cargoes along the axoneme of eukaryotic cilia and flagella. Both dyneins operate as large ATP-driven motor complexes, whose dysfunction is associated with a group of human disorders. But how similar are their mechanisms of action and regulation? To examine this question, this review focuses on recent advances in dynein-1 and -2 research, and probes to what extent the emerging principles of dynein-1 transport could apply to or differ from those of the less well-understood dynein-2 mechanoenzyme.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2017) 45 (1): 37–49.
Published: 15 February 2017
..., these activities require activation of AURKA in early G1, and the mechanisms of activation are much less well defined than those in mitosis. A better understanding of the control of AURKA activity and the role of AURKA at cilia are both important in optimizing the efficacy and interpreting potential...
Abstract
Overexpression of the Aurora kinase A (AURKA) is oncogenic in many tumors. Many studies of AURKA have focused on activities of this kinase in mitosis, and elucidated the mechanisms by which AURKA activity is induced at the G2/M boundary through interactions with proteins such as TPX2 and NEDD9. These studies have informed the development of small molecule inhibitors of AURKA, of which a number are currently under preclinical and clinical assessment. While the first activities defined for AURKA were its control of centrosomal maturation and organization of the mitotic spindle, an increasing number of studies over the past decade have recognized a separate biological function of AURKA, in controlling disassembly of the primary cilium, a small organelle protruding from the cell surface that serves as a signaling platform. Importantly, these activities require activation of AURKA in early G1, and the mechanisms of activation are much less well defined than those in mitosis. A better understanding of the control of AURKA activity and the role of AURKA at cilia are both important in optimizing the efficacy and interpreting potential downstream consequences of AURKA inhibitors in the clinic. We here provide a current overview of proteins and mechanisms that have been defined as activating AURKA in G1, based on the study of ciliary disassembly.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2016) 44 (6): 1745–1751.
Published: 02 December 2016
... disease affects millions of people worldwide and although pharmacological treatments exist for some conditions, there are still patients whose only option is kidney dialysis and kidney transplantation. In the past 10 years, certain chronic kidney diseases have been reclassified as ciliopathies. Cilia in...
Abstract
Biomarkers, the measurable indicators of biological conditions, are fast becoming a popular approach in providing information to track disease processes that could lead to novel therapeutic interventions for chronic conditions. Inherited, chronic kidney disease affects millions of people worldwide and although pharmacological treatments exist for some conditions, there are still patients whose only option is kidney dialysis and kidney transplantation. In the past 10 years, certain chronic kidney diseases have been reclassified as ciliopathies. Cilia in the kidney are antenna-like, sensory organelles that are required for signal transduction. One of the signalling pathways that requires the primary cilium in the kidney is Wnt signalling and it has three components such as canonical Wnt, non-canonical Wnt/planar cell olarity (PCP) and non-canonical Wnt/Ca 2+ signalling. Identification of the novel role of ATM INteractor (ATMIN) as an effector molecule in the non-canonical Wnt/PCP pathway has intrigued us to investigate its potential role in chronic kidney disease. ATMIN could thus be an important biomarker in disease prognosis and treatment that might lighten the burden of chronic kidney disease and also affect on its progression.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2016) 44 (6): 1753–1759.
Published: 02 December 2016
... primordium and subsequent steps in the outgrowth of the mandibular skeleton. We then determine the critical tissue interactions using mice carrying a conditional mutation in the cilia gene Ofd1 . Our studies highlight the usefulness of the Ofd1 mouse model and illustrate long-term possibilities for...
Abstract
Defects in the development of the mandible can lead to micrognathia, or small jaw, which manifests in ciliopathic conditions, such as orofaciodigital syndrome, Meckel–Gruber syndrome, and Bardet–Biedl syndrome. Although micrognathia occurs frequently in human and mouse ciliopathies, it has been difficult to pinpoint the underlying cellular causes. In this mini-review, we shed light on the tissue-specific contributions to ciliary dysfunction in the development of the mandible. First, we outline the steps involved in setting up the jaw primordium and subsequent steps in the outgrowth of the mandibular skeleton. We then determine the critical tissue interactions using mice carrying a conditional mutation in the cilia gene Ofd1 . Our studies highlight the usefulness of the Ofd1 mouse model and illustrate long-term possibilities for understanding the cellular and biochemical events underlying micrognathia.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2016) 44 (5): 1273–1280.
Published: 19 October 2016
...Louise A. Stephen; Shehab Ismail Primary cilia are hair-like microtubule-based organelles that can be found on almost all human cell types. Although the cilium is not separated from the cell by membranes, their content is different from that of the cell body and their membrane composition is...
Abstract
Primary cilia are hair-like microtubule-based organelles that can be found on almost all human cell types. Although the cilium is not separated from the cell by membranes, their content is different from that of the cell body and their membrane composition is distinct from that of the plasma membrane. Here, we will introduce a molecular machinery that shuttles and sorts lipid-modified proteins to the cilium, thus contributing in maintaining its distinct composition. The mechanism involves the binding of the GDI-like solubilising factors, uncoordinated (UNC)119a, UNC119b and PDE6D, to the lipid-modified ciliary cargo and the specific release of the cargo in the cilia by the ciliary small G-protein Arl3 in a GTP-dependent manner.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2016) 44 (5): 1227–1234.
Published: 19 October 2016
...Samuel M. O'Toole; J. Paul Chapple Primary cilia are sensory organelles that play a role as signalling hubs. Disruption of primary cilia structure and function is increasingly recognised in a range of cancers, with a growing body of evidence suggesting that ciliary disruption contributes to...
Abstract
Primary cilia are sensory organelles that play a role as signalling hubs. Disruption of primary cilia structure and function is increasingly recognised in a range of cancers, with a growing body of evidence suggesting that ciliary disruption contributes to tumourigenesis. This review considers the role of primary cilia in the pathogenesis of endocrine-related cancers.
Articles
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2016) 44 (5): 1265–1271.
Published: 19 October 2016
...Robert F. Shearer; Darren N. Saunders Primary cilia form at the surface of most vertebrate cell types, where they are essential signalling antennae for signal transduction pathways important for development and cancer, including Hedgehog. The importance of primary cilia in development is clearly...
Abstract
Primary cilia form at the surface of most vertebrate cell types, where they are essential signalling antennae for signal transduction pathways important for development and cancer, including Hedgehog. The importance of primary cilia in development is clearly demonstrated by numerous disorders (known as ciliopathies) associated with disrupted cilia formation (ciliogenesis). Recent advances describing functional regulators of the primary cilium highlight an emerging role for the ubiquitin–proteasome system (UPS) as a key regulator of ciliogenesis. Although there are well-documented examples of E3 ubiquitin ligases and deubiquitases in the regulation of cilia proteins, many putative components remain unvalidated. This review explores current understanding of how the UPS influences primary cilia formation, and also how recent screen data have identified more putative regulators of the UPS. Emerging research has identified many promising leads in the search for regulators of this important organelle and may identify potential novel therapeutic targets for intervention in cancer and other disease contexts.
Articles
David A. Parfitt, Amelia Lane, Conor Ramsden, Katarina Jovanovic, Peter J. Coffey, Alison J. Hardcastle, Michael E. Cheetham
Journal:
Biochemical Society Transactions
Biochem Soc Trans (2016) 44 (5): 1245–1251.
Published: 19 October 2016
...David A. Parfitt; Amelia Lane; Conor Ramsden; Katarina Jovanovic; Peter J. Coffey; Alison J. Hardcastle; Michael E. Cheetham The photoreceptor cells in the retina have a highly specialised sensory cilium, the outer segment (OS), which is important for detecting light. Mutations in cilia-related...
Abstract
The photoreceptor cells in the retina have a highly specialised sensory cilium, the outer segment (OS), which is important for detecting light. Mutations in cilia-related genes often result in retinal degeneration. The ability to reprogramme human cells into induced pluripotent stem cells and then differentiate them into a wide range of different cell types has revolutionised our ability to study human disease. To date, however, the challenge of producing fully differentiated photoreceptors in vitro has limited the application of this technology in studying retinal degeneration. In this review, we will discuss recent advances in stem cell technology and photoreceptor differentiation. In particular, the development of photoreceptors with rudimentary OS that can be used to understand disease mechanisms and as an important model to test potential new therapies for inherited retinal ciliopathies.