The primary cilium at a glance.
Ontology highlight
ABSTRACT:
SUBMITTER: Satir P
PROVIDER: S-EPMC2818190 | biostudies-literature | 2010 Feb
REPOSITORIES: biostudies-literature
Publications
The primary cilium at a glance.
Satir Peter P Pedersen Lotte B LB Christensen Søren T ST
Journal of cell science 20100201 Pt 4
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Project description:Primary cilia are hair-like organelles and play crucial roles in vertebrate development, organogenesis, health, and many genetic disorders. A primary cilium is a mechano-sensory organelle that responds to mechanical stimuli in the micro-environment. A cilium is also a chemosensor that senses chemical signals surrounding a cell. The overall function of a cilium is therefore to act as a communication hub to transfer extracellular signals into intracellular responses. Although intracellular calcium has been one of the most studied signaling messengers that transmit extracellular signals into the cells, calcium signaling by various ion channels remains a topic of interest in the field. This may be due to a broad spectrum of cilia functions that are dependent on or independent of utilizing calcium as a second messenger. We therefore revisit and discuss the calcium-dependent and calcium-independent ciliary signaling pathways of Hedgehog, Wnt, PDGFR, Notch, TGF-β, mTOR, OFD1 autophagy, and other GPCR-associated signaling. All of these signaling pathways play crucial roles in various cellular processes, such as in organ and embryonic development, cardiac functioning, planar cell polarity, transactivation, differentiation, the cell cycle, apoptosis, tissue homeostasis, and the immune response.
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Project description:The primary cilium is a central signaling hub in cell proliferation and differentiation and is built and disassembled every cell cycle in many animal cells. Disassembly is critically important, as misregulation or delay of cilia loss leads to cell cycle defects. The physical means by which cilia are lost are poorly understood but are thought to involve resorption of ciliary components into the cell body. To investigate cilium loss in mammalian cells, we used live-cell imaging to comprehensively characterize individual events. The predominant mode of cilium loss was rapid deciliation, in which the membrane and axoneme of the cilium was shed from the cell. Gradual resorption was also observed, as well as events in which a period of gradual resorption was followed by rapid deciliation. Deciliation resulted in intact shed cilia that could be recovered from culture medium and contained both membrane and axoneme proteins. We modulated levels of katanin and intracellular calcium, two putative regulators of deciliation, and found that excess katanin promotes cilia loss by deciliation, independently of calcium. Together, these results suggest that mammalian ciliary loss involves a tunable decision between deciliation and resorption.
| S-EPMC6699714 | biostudies-literature
Project description:The primary cilium is able to maintain a specific protein composition, which is critical for its function as a signaling organelle. Here we introduce a system to synchronize biosynthetic trafficking of ciliary proteins that is based on conditional aggregation domains (CADs). This approach enables to create a wave of ciliary proteins that are transported together, which opens novel avenues for visualizing and studying ciliary import mechanisms. By using somatostatin receptor 3 (SSTR3) as model protein we studied intracellular transport and ciliary import with high temporal and spatial resolution in epithelial Madin-Darby canine kidney (MDCK) cells. This yielded the interesting discovery that SSTR3, besides being transported to the primary cilium, is also targeted to the basolateral plasma membrane. In addition, we found a similar behavior for another ciliary protein, nephrocystin-3 (NPHP3), thus suggesting a potential correlation between ciliary and basolateral trafficking. Furthermore, our CAD-based system allowed assembling a large dataset in which apical and basolateral surface SSTR3 signals could be compared to ciliary SSTR3 signals on a single cell level. This enabled to generate novel complementary evidence for the previously proposed lateral import mechanism of SSTR3 into the cilium along the plasma membrane.
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Project description:The primary cilium is an important signaling organelle critical for normal development and tissue homeostasis. Its small dimensions and complexity necessitate advanced imaging approaches to uncover the molecular mechanisms behind its function. Here, we outline how single-molecule fluorescence microscopy can be used for tracking molecular dynamics and interactions and for super-resolution imaging of nanoscale structures in the primary cilium. Specifically, we describe in detail how to capture and quantify the 2D dynamics of individual transmembrane proteins PTCH1 and SMO and how to map the 3D nanoscale distributions of the inversin compartment proteins INVS, ANKS6, and NPHP3. This protocol can, with minor modifications, be adapted for studies of other proteins and cell lines to further elucidate the structure and function of the primary cilium at the molecular level.
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Project description:Osteocytes are accepted as the primary mechanosensing cell in bone, but how they translate mechanical signals into biochemical signals remains unclear. Adenylyl cyclases (AC) are enzymes that catalyze the production of second messenger cyclic adenosine monophosphate (cAMP). Osteocytes display a biphasic, cAMP response to fluid shear with an initial decrease in cAMP concentrations and then an increased concentration after sustained mechanical stimulation. To date, AC6, a calcium-inhibited AC, is the primary isoform studied in bone. Since osteocytes are calcium-responsive mechanosensors, we asked if a calcium-stimulated isoform contributes to mechanotransduction. Using a transcriptomic dataset of MLO-Y4 osteocyte-like cells from the NIH Gene Expression Omnibus, we identified AC3 as the only calcium-stimulated isoform expressed. We show that inhibiting AC3 in MLO-Y4 cells results in decreased cAMP-signaling with fluid shear and increased osteogenic response to fluid flow (measured as Ptgs2 expression) of longer durations, but not shorter. AC3 likely contributes to osteocyte mechanotransduction through a signaling axis involving the primary cilium and GSK3β. We demonstrate that AC3 localizes to the primary cilium, as well as throughout the cytosol and that fluid-flow regulation of primary cilia length is altered with an AC3 knockdown. Regulation of GSK3β is downstream of the primary cilium and cAMP signaling, and with western blots we found that GSK3β inhibition by phosphorylation is increased after fluid shear in AC3 knockdown groups. Our data show that AC3 contributes to osteocyte mechanotransduction and warrants further investigation to pave the way to identifying new therapeutic targets to treat bone disease like osteoporosis.
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Project description:Introduction: Atopic dermatitis (AD) is a common allergic eczema that affects up to 10% of adults in developed countries. Immune cells in the epidermis, namely, Langerhans cells (LCs), contribute to the pathogenesis of AD, although their exact role(s) in disease remain unclear. Methods: We performed immunostaining on human skin and peripheral blood mononuclear cells (PBMCs) and visualized primary cilium. Result and discussion: We show that human dendritic cells (DCs) and LCs have a previously unknown primary cilium-like structure. The primary cilium was assembled during DC proliferation in response to the Th2 cytokine GM-CSF, and its formation was halted by DC maturation agents. This suggests that the role of primary cilium is to transduce proliferation signaling. The platelet-derived growth factor receptor alpha (PDGFRα) pathway, which is known for transducing proliferation signals in the primary cilium, promoted DC proliferation in a manner dependent on the intraflagellar transport (IFT) system. We also examined the epidermal samples from AD patients, and observed aberrantly ciliated LCs and keratinocytes in immature and proliferating states. Our results identify a potential relationship between the primary cilium and allergic skin barrier disorders, and suggest that targeting the primary cilium may contribute to treating AD.
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Project description:Myofibroblasts, the culprit of organ fibrosis, can originate from mesenchymal and epithelial precursors through fibroblast-myofibroblast and epithelial-myofibroblast transition (EMyT). Because certain ciliopathies are associated with fibrogenesis, we sought to explore the fate and potential role of the primary cilium during myofibroblast formation. Here we show that myofibroblast transition from either precursor results in the loss of the primary cilium. During EMyT, initial cilium growth is followed by complete deciliation. Both EMyT and cilium loss require two-hit conditions: disassembly/absence of intercellular contacts and transforming growth factor-β1 (TGFβ) exposure. Loss of E-cadherin-dependent junctions induces cilium elongation, whereas both stimuli are needed for deciliation. Accordingly, in a scratch-wounded epithelium, TGFβ provokes cilium loss exclusively along the wound edge. Increased contractility, a key myofibroblast feature, is necessary and sufficient for deciliation, since constitutively active RhoA, Rac1, or myosin triggers, and down-regulation of myosin or myocardin-related transcription factor prevents, this process. Sustained myosin phosphorylation and consequent deciliation are mediated by a Smad3-, Rac1-, and reactive oxygen species-dependent process. Transitioned myofibroblasts exhibit impaired responsiveness to platelet-derived growth factor-AA and sonic hedgehog, two cilium-associated stimuli. Although the cilium is lost during EMyT, its initial presence contributes to the transition. Thus myofibroblasts represent a unique cilium-less entity with profoundly reprogrammed cilium-related signaling.
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Project description:Cilia are complex structures that have garnered interest because of their roles in vertebrate development and their involvement in human genetic disorders. In contrast to multicellular invertebrates in which cilia are restricted to specific cell types, these organelles are found almost ubiquitously in vertebrate cells, where they serve a diverse set of signaling functions. Here, we highlight properties of vertebrate cilia, with particular emphasis on their relationship with other subcellular structures, and explore the physiological consequences of ciliary dysfunction.
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Project description:The primary cilium (PC) has emerged as an indispensable cellular antenna essential for signal transduction of important cell signaling pathways. The rapid acquisition of knowledge about PC biology has raised attention to PC as a therapeutic target in some neurological and psychiatric diseases. However, the role of PC in oligodendrocytes and its participation in myelination/remyelination remain poorly understood. Oligodendrocyte precursor cells (OPCs) give rise to oligodendrocytes during central nervous system (CNS) development. In adult, a small percentage of OPCs remains as undifferentiated cells located sparsely in the different regions of the CNS. These cells can regenerate oligodendrocytes and participate to certain extent in remyelination. This study aims characterize PC in oligodendrocyte lineage cells during post-natal development and in a mouse model of demyelination/remyelination. We show heterogeneity in the frequency of cilium presence on OPCs, depending on culture conditions in vitro and cerebral regions in vivo during development and demyelination/remyelination. In vitro, Lithium chloride (LiCl), Forskolin and Chloral Hydrate differentially affect cilium, depending on culture environment and PC length correlates with the cell differentiation state. Beside the role of PC as a keeper of cell proliferation, our results suggest its involvement in myelination/remyelination.
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Project description:Zfp423 encodes a 30-zinc finger transcription factor that intersects several canonical signaling pathways. Zfp423 mutations result in ciliopathy-related phenotypes, including agenesis of the cerebellar vermis in mice and Joubert syndrome (JBTS19) and nephronophthisis (NPHP14) in humans. Unlike most ciliopathy genes, Zfp423 encodes a nuclear protein and its developmental expression is complex, leading to alternative proposals for cellular mechanisms. Here we show that Zfp423 is expressed by cerebellar granule cell precursors, that loss of Zfp423 in these precursors leads to cell-intrinsic reduction in proliferation, loss of response to Shh, and primary cilia abnormalities that include diminished frequency of both Smoothened and IFT88 localization. Loss of Zfp423 alters expression of several genes encoding key cilium components, including increased expression of Tulp3. Tulp3 is a direct binding target of Zfp423 and reducing the overexpression of Tulp3 in Zfp423-deficient cells suppresses Smoothened translocation defects. These results define Zfp423 deficiency as a bona fide ciliopathy, acting upstream of Shh signaling, and indicate a mechanism intrinsic to granule cell precursors for the resulting cerebellar hypoplasia.
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