scholarly journals The Roles of Primary Cilia in Cardiovascular Diseases

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 233 ◽  
Author(s):  
Rajasekharreddy Pala ◽  
Maha Jamal ◽  
Qamar Alshammari ◽  
Surya Nauli
Keyword(s):  
Cardiovascular Diseases ◽  
Primary Cilia ◽  
Cell Types ◽  
Molecular Defects ◽  
Flow Sensing ◽  
Intracellular Signals ◽  
Wide Range ◽  
No Signaling ◽  
Vascular Endothelia ◽  
And Function

Primary cilia are microtubule-based organelles found in most mammalian cell types. Cilia act as sensory organelles that transmit extracellular clues into intracellular signals for molecular and cellular responses. Biochemical and molecular defects in primary cilia are associated with a wide range of diseases, termed ciliopathies, with phenotypes ranging from polycystic kidney disease, liver disorders, mental retardation, and obesity to cardiovascular diseases. Primary cilia in vascular endothelia protrude into the lumen of blood vessels and function as molecular switches for calcium (Ca2+) and nitric oxide (NO) signaling. As mechanosensory organelles, endothelial cilia are involved in blood flow sensing. Dysfunction in endothelial cilia contributes to aberrant fluid-sensing and thus results in vascular disorders, including hypertension, aneurysm, and atherosclerosis. This review focuses on the most recent findings on the roles of endothelial primary cilia within vascular biology and alludes to the possibility of primary cilium as a therapeutic target for cardiovascular disorders.

scholarly journals Mapping calcium dynamics in a developing tubular structure

2020 ◽  
Author(s):  
Jorgen Hoyer ◽  
Morsal Saba ◽  
Daniel Dondorp ◽  
Kushal Kolar ◽  
Riccardo Esposito ◽  
...  
Keyword(s):  
Cell Types ◽  
Feedback Mechanism ◽  
Adult Brain ◽  
Actin Dynamics ◽  
Cytoskeletal Network ◽  
Notochord Cell ◽  
Wide Range ◽  
Store Operated Calcium Entry ◽  
And Function ◽  
Cell Intercalation

AbstractCalcium is a ubiquitous and versatile second messenger that plays a central role in the development and function of a wide range of cell types, tissues and organs. Despite significant recent progress in the understanding of calcium (Ca2+) signalling in organs such as the developing and adult brain, we have relatively little knowledge of the contribution of Ca2+ to the development of tubes, structures widely present in multicellular organisms. Here we image Ca2+ dynamics in the developing notochord of Ciona intestinalis. We show that notochord cells exhibit distinct Ca2+ dynamics during specific morphogenetic events such as cell intercalation, cell elongation and tubulogenesis. We used an optogenetically controlled Ca2+ actuator to show that sequestration of Ca2+ results in defective notochord cell intercalation, and pharmacological inhibition to reveal that stretch-activated ion channels (SACs), inositol triphosphate receptor (IP3R) signalling, Store Operated Calcium Entry (SOCE), Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and gap junctions are required for regulating notochord Ca2+ activity during tubulogenesis. Cytoskeletal rearrangements drive the cell shape changes that accompany tubulogenesis. In line with this, we show that Ca2+ signalling modulates reorganization of the cytoskeletal network across the morphogenetic events leading up to and during tubulogenesis of the notochord. We additionally demonstrate that perturbation of the actin cytoskeleton drastically remodels Ca2+ dynamics, suggesting a feedback mechanism between actin dynamics and Ca2+ signalling during notochord development. This work provides a framework to quantitatively define how Ca2+ signalling regulates tubulogenesis using the notochord as model organ, a defining structure of all chordates.

scholarly journals Symplekin, a novel type of tight junction plaque protein.

1996 ◽  
Vol 134 (4) ◽  
pp. 1003-1018 ◽  
Author(s):  
B H Keon ◽  
S Schäfer ◽  
C Kuhn ◽  
C Grund ◽  
W W Franke
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Sertoli Cells ◽  
Light And Electron Microscopy ◽  
Cell Types ◽  
Calculated Molecular Weight ◽  
Zonula Occludens ◽  
Cytoplasmic Face ◽  
Wide Range ◽  
Vascular Endothelia

Using a monoclonal antibody we have identified and cDNA-cloned a novel type of protein localized, by light and electron microscopy, to the plaque associated with the cytoplasmic face of the tight junction-containing zone (zonula occludens) of polar epithelial cells and of Sertoli cells of testis, but absent from the junctions of vascular endothelia. The approximately 3.7-kb mRNA encodes a polypeptide of 1142 amino acids (calculated molecular weight 126.5 kD, pI 6.25), for which the name "symplekin" (from Greek sigma upsilon mu pi lambda epsilon kappa epsilon iota, nu, to tie together, to weave, to be intertwined) is proposed. However, both the mRNA and the protein can also be detected in a wide range of cell types that do not form tight junctions or are even completely devoid of any stable cell contacts. Careful analyses have revealed that the protein occurs in all these diverse cells in the nucleoplasm, and only in those cells forming tight junctions is it recruited, partly but specifically, to the plaque structure of the zonula occludens. We discuss symplekin as a representative of a group of dual residence proteins which occur and probably function in the nucleus as well as in the plaques exclusive for either tight junctions, adherens junctions, or desmosomes.

scholarly journals Structure and function of the immune system in the spleen

2019 ◽  
Vol 4 (33) ◽  
pp. eaau6085 ◽  
Author(s):  
Steven M. Lewis ◽  
Adam Williams ◽  
Stephanie C. Eisenbarth
Keyword(s):  
Cell Types ◽  
Structure And Function ◽  
Lymphoid Organ ◽  
The Body ◽  
Human Spleen ◽  
Cell Clearance ◽  
Wide Range ◽  
Abnormal Cells ◽  
Cell Organization ◽  
And Function

The spleen is the largest secondary lymphoid organ in the body and, as such, hosts a wide range of immunologic functions alongside its roles in hematopoiesis and red blood cell clearance. The physical organization of the spleen allows it to filter blood of pathogens and abnormal cells and facilitate low-probability interactions between antigen-presenting cells (APCs) and cognate lymphocytes. APCs specific to the spleen regulate the T and B cell response to these antigenic targets in the blood. This review will focus on cell types, cell organization, and immunologic functions specific to the spleen and how these affect initiation of adaptive immunity to systemic blood-borne antigens. Potential differences in structure and function between mouse and human spleen will also be discussed.

scholarly journals Bone Anabolic Effects of Soluble Si:In VitroStudies with Human Mesenchymal Stem Cells and CD14+ Osteoclast Precursors

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
J. Costa-Rodrigues ◽  
S. Reis ◽  
A. Castro ◽  
M. H. Fernandes
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Plasma Levels ◽  
Human Mesenchymal Stem Cells ◽  
Cell Types ◽  
Osteoclast Precursors ◽  
Wide Range ◽  
Basal Plasma ◽  
Important Player ◽  
And Function

Silicon (Si) is indispensable for many cellular processes including bone tissue metabolism. In this work, the effects of Si on human osteogenesis and osteoclastogenesis were characterized. Human mesenchymal stem cells (hMSC) and CD14+ stem cells, as osteoblast and osteoclast precursors, were treated with a wide range of Si concentrations, covering the physiological plasma levels. Si promoted a dose-dependent increase in hMSC proliferation, differentiation, and function, at levels similar to the normal basal plasma levels. Additionally, a decrease in the expression of the osteoclastogenic activators M-CSF and RANKL was observed. Also, Si elicited a decrease in osteoclastogenesis, which became significant at higher concentrations, as those observed after meals. Among the intracellular mechanisms studied, an upregulation of MEK and PKC signalling pathways was observed in both cell types. In conclusion, Si appears to have a direct positive effect on human osteogenesis, at basal plasma levels. On the other hand, it also seemed to be an inhibitor of osteoclastogenesis, but at higher concentrations, though yet in the physiological range. Further, an indirect effect of Si on osteoclastogenesis may also occur, through a downregulation of M-CSF and RANKL expression by osteoblasts. Thus, Si may be an important player in bone anabolic regenerative approaches.

scholarly journals The Exocyst Protein Sec10 Is Necessary for Primary Ciliogenesis and Cystogenesis In Vitro

2009 ◽  
Vol 20 (10) ◽  
pp. 2522-2529 ◽  
Author(s):  
Xiaofeng Zuo ◽  
Wei Guo ◽  
Joshua H. Lipschutz
Keyword(s):  
Membrane Trafficking ◽  
Primary Cilia ◽  
Collagen Matrix ◽  
Cell Types ◽  
Flow Sensing ◽  
Transmission Electron ◽  
Autosomal Dominant Polycystic Kidney ◽  
Renal Tubular ◽  
Darby Canine Kidney

Primary cilia are found on many epithelial cell types, including renal tubular epithelial cells, in which they are felt to participate in flow sensing and have been linked to the pathogenesis of cystic renal disorders such as autosomal dominant polycystic kidney disease. We previously localized the exocyst, an eight-protein complex involved in membrane trafficking, to the primary cilium of Madin-Darby canine kidney cells and showed that it was involved in cystogenesis. Here, using short hairpin RNA (shRNA) to knockdown exocyst expression and stable transfection to induce exocyst overexpression, we show that the exocyst protein Sec10 regulates primary ciliogenesis. Using immunofluorescence, scanning, and transmission electron microscopy, primary cilia containing only basal bodies are seen in the Sec10 knockdown cells, and increased ciliogenesis is seen in Sec10-overexpressing cells. These phenotypes do not seem to be because of gross changes in cell polarity, as apical, basolateral, and tight junction proteins remain properly localized. Sec10 knockdown prevents normal cyst morphogenesis when the cells are grown in a collagen matrix, whereas Sec10 overexpression results in increased cystogenesis. Transfection with human Sec10 resistant to the canine shRNA rescues the phenotype, demonstrating specificity. Finally, Par3 was recently shown to regulate primary cilia biogenesis. Par3 and the exocyst colocalized by immunofluorescence and coimmunoprecipitation, consistent with a role for the exocyst in targeting and docking vesicles carrying proteins necessary for primary ciliogenesis.

scholarly journals Morphology and function of three VIP-expressing amacrine cell types in the mouse retina

2015 ◽  
Vol 114 (4) ◽  
pp. 2431-2438 ◽  
Author(s):  
Alejandro Akrouh ◽  
Daniel Kerschensteiner
Keyword(s):  
Mammalian Species ◽  
Plexiform Layer ◽  
Amacrine Cells ◽  
Cell Types ◽  
Mouse Retina ◽  
Inner Plexiform Layer ◽  
Light Responses ◽  
Wide Range ◽  
Asymmetric Distributions ◽  
And Function

Amacrine cells (ACs) are the most diverse class of neurons in the retina. The variety of signals provided by ACs allows the retina to encode a wide range of visual features. Of the 30–50 AC types in mammalian species, few have been studied in detail. Here, we combine genetic and viral strategies to identify and to characterize morphologically three vasoactive intestinal polypeptide-expressing GABAergic AC types (VIP1-, VIP2-, and VIP3-ACs) in mice. Somata of VIP1- and VIP2-ACs reside in the inner nuclear layer and somata of VIP3-ACs in the ganglion cell layer, and they show asymmetric distributions along the dorsoventral axis of the retina. Neurite arbors of VIP-ACs differ in size (VIP1-ACs ≈ VIP3-ACs > VIP2-ACs) and stratify in distinct sublaminae of the inner plexiform layer. To analyze light responses and underlying synaptic inputs, we target VIP-ACs under 2-photon guidance for patch-clamp recordings. VIP1-ACs depolarize strongly to light increments (ON) over a wide range of stimulus sizes but show size-selective responses to light decrements (OFF), depolarizing to small and hyperpolarizing to large stimuli. The switch in polarity of OFF responses is caused by pre- and postsynaptic surround inhibition. VIP2- and VIP3-ACs both show small depolarizations to ON stimuli and large hyperpolarizations to OFF stimuli but differ in their spatial response profiles. Depolarizations are caused by ON excitation outweighing ON inhibition, whereas hyperpolarizations result from pre- and postsynaptic OFF-ON crossover inhibition. VIP1-, VIP2-, and VIP3-ACs thus differ in response polarity and spatial tuning and contribute to the diversity of inhibitory and neuromodulatory signals in the retina.

scholarly journals Phosphoinositide lipids in primary cilia biology

2020 ◽  
Vol 477 (18) ◽  
pp. 3541-3565
Author(s):  
Sarah E. Conduit ◽  
Bart Vanhaesebroeck
Keyword(s):  
Primary Cilia ◽  
Critical Role ◽  
Phospholipid Composition ◽  
Cell Types ◽  
Phosphoinositide Metabolism ◽  
Lipid Phosphatases ◽  
Regulatory Enzymes ◽  
Lipid Species ◽  
Cilia Formation ◽  
And Function

Primary cilia are solitary signalling organelles projecting from the surface of most cell types. Although the ciliary membrane is continuous with the plasma membrane it exhibits a unique phospholipid composition, a feature essential for normal cilia formation and function. Recent studies have illustrated that distinct phosphoinositide lipid species localise to specific cilia subdomains, and have begun to build a ‘phosphoinositide map’ of the cilium. The abundance and localisation of phosphoinositides are tightly regulated by the opposing actions of lipid kinases and lipid phosphatases that have also been recently discovered at cilia. The critical role of phosphoinositides in cilia biology is highlighted by the devastating consequences of genetic defects in cilia-associated phosphoinositide regulatory enzymes leading to ciliopathy phenotypes in humans and experimental mouse and zebrafish models. Here we provide a general introduction to primary cilia and the roles phosphoinositides play in cilia biology. In addition to increasing our understanding of fundamental cilia biology, this rapidly expanding field may inform novel approaches to treat ciliopathy syndromes caused by deregulated phosphoinositide metabolism.

scholarly journals Flagellar Synchronization Is a Simple Alternative to Cell Cycle Synchronization for Ciliary and Flagellar Studies

mSphere ◽  
2017 ◽  
Vol 2 (2) ◽  
Author(s):  
Soumita Dutta ◽  
Prachee Avasthi
Keyword(s):  
Cell Cycle ◽  
Chlamydomonas Reinhardtii ◽  
Cell Types ◽  
Model System ◽  
Content Type ◽  
Cell Synchronization ◽  
Cilium Formation ◽  
Wide Range ◽  
Cilia And Flagella ◽  
And Function

ABSTRACT Cilia and flagella are highly conserved antenna-like organelles that found in nearly all mammalian cell types. They perform sensory and motile functions contributing to numerous physiological and developmental processes. Defects in their assembly and function are implicated in a wide range of human diseases ranging from retinal degeneration to cancer. Chlamydomonas reinhardtii is an algal model system for studying mammalian cilium formation and function. Here, we report a simple synchronization method that allows detection of small changes in ciliary length by minimizing variability in the population. We find that this method alters the key relationship between cell size and the amount of protein accumulated for flagellar growth. This provides a rapid alternative to traditional methods of cell synchronization for uncovering novel regulators of cilia. The unicellular green alga Chlamydomonas reinhardtii is an ideal model organism for studies of ciliary function and assembly. In assays for biological and biochemical effects of various factors on flagellar structure and function, synchronous culture is advantageous for minimizing variability. Here, we have characterized a method in which 100% synchronization is achieved with respect to flagellar length but not with respect to the cell cycle. The method requires inducing flagellar regeneration by amputation of the entire cell population and limiting regeneration time. This results in a maximally homogeneous distribution of flagellar lengths at 3 h postamputation. We found that time-limiting new protein synthesis during flagellar synchronization limits variability in the unassembled pool of limiting flagellar protein and variability in flagellar length without affecting the range of cell volumes. We also found that long- and short-flagella mutants that regenerate normally require longer and shorter synchronization times, respectively. By minimizing flagellar length variability using a simple method requiring only hours and no changes in media, flagellar synchronization facilitates the detection of small changes in flagellar length resulting from both chemical and genetic perturbations in Chlamydomonas. This method increases our ability to probe the basic biology of ciliary size regulation and related disease etiologies. IMPORTANCE Cilia and flagella are highly conserved antenna-like organelles that found in nearly all mammalian cell types. They perform sensory and motile functions contributing to numerous physiological and developmental processes. Defects in their assembly and function are implicated in a wide range of human diseases ranging from retinal degeneration to cancer. Chlamydomonas reinhardtii is an algal model system for studying mammalian cilium formation and function. Here, we report a simple synchronization method that allows detection of small changes in ciliary length by minimizing variability in the population. We find that this method alters the key relationship between cell size and the amount of protein accumulated for flagellar growth. This provides a rapid alternative to traditional methods of cell synchronization for uncovering novel regulators of cilia.

Primary Cilia Mediate Intracellular cAMP Responses in Bone Cells Exposed to Dynamic Fluid Flow

2008 ◽  
Author(s):  
Ronald Y. Kwon ◽  
Sara Temiyasathit ◽  
Padmaja Tummala ◽  
Clarence Quah ◽  
Christopher R. Jacobs
Keyword(s):  
Fluid Flow ◽  
Primary Cilia ◽  
Bone Structure ◽  
Bone Cells ◽  
Cyclic Adenosine Monophosphate ◽  
Second Messenger ◽  
Adenosine Monophosphate ◽  
Cell Types ◽  
Intracellular Camp ◽  
And Function

It is well accepted that fluid flow is an important mechanical signal in regulating bone structure and function. Primary cilia, which are non-motile, microtubule based organelles that extend from the centrosome and project into extracellular space in many cell types, have recently been shown to mediate fluid flow-induced osteogenic responses in MLO-Y4 osteocyte-like cells [1]. However, primary cilia did not mediate increases in intracellular Ca2+ concentration, and the second messenger system(s) involved in primary cilia-mediated mechanosensing has yet to be elucidated. In this study, our goals were to (1) determine whether exposing bone cells to oscillatory fluid flow modulates intracellular levels of cyclic adenosine monophosphate (cAMP), another ubiquitous second messenger molecule, and (2) investigate whether this modulation may be mediated by primary cilia.

scholarly journals Signaling roles of phosphoinositides in the retina

2020 ◽  
pp. jlr.TR120000806 ◽  
Author(s):  
Raju V. S. Rajala
Keyword(s):  
Cell Types ◽  
Cellular Functions ◽  
Parent Molecule ◽  
Phosphoinositide Signaling ◽  
Wide Range ◽  
The Many ◽  
And Function ◽  
Different Cell Types

The field of phosphoinositide signaling has expanded significantly in recent years. Phosphoinositides (PIs) are universal signaling molecules that directly interact with membrane proteins or with cytosolic proteins containing domains that directly bind phosphoinositides and are recruited to cell membranes. Through the activities of PI kinases and PI phosphatases, seven distinct phosphoinositide lipid molecules are formed from the parent molecule phosphatidylinositol. PI signals regulate a wide range of cellular functions, including cytoskeletal assembly, membrane binding and fusion, ciliogenesis, vesicular transport, and signal transduction. Given the many excellent reviews on phosphoinositide kinases, phosphoinositide phosphatases, and PIs in general, in this review, we discuss recent studies and advances in PI lipid signaling in the retina. We specifically focus on PI lipids from vertebrate (e.g. bovine, rat, mice, toad, and zebrafish) and invertebrate (e.g. drosophila, horseshoe crab, and squid) retinas. We also discuss the importance of PIs revealed from animal models and human diseases, and methods to study PI levels both in vitro and in vivo. We propose that future studies should investigate the function and mechanism of activation of PI-modifying enzymes/phosphatases and further unravel PI regulation and function in the different cell types of the retina.

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