The primary cilium as sensor of fluid flow: new building blocks to the model. A review in the theme: cell signaling: proteins, pathways and mechanisms.

The primary cilium is an extraordinary organelle. For many years, it had the full attention of only a few dedicated scientists fascinated by its uniqueness. Unexpectedly, after decades of obscurity, it has moved very quickly into the limelight with the increasing evidence of its central role in the many genetic variations that lead to what are now known as ciliopathies. These studies implicated unique biological functions of the primary cilium, which are not completely straightforward. In parallel, and initially completely unrelated to the ciliopathies, the primary cilium was characterized functionally as an organelle that makes cells more susceptible to changes in fluid flow. Thus the primary cilium was suggested to function as a flow-sensing device. This characterization has been substantiated for many epithelial cell types over the years. Nevertheless, part of the central mechanism of signal transduction has not been explained, largely because of the substantial technical challenges of working with this delicate organelle. The current review considers the recent advances that allow us to fill some of the holes in the model of signal transduction in cilium-mediated responses to fluid flow and to pursue the physiological implications of this peculiar organelle.

[1]  R. Chambrey,et al.  Localization of connexin 30 in the luminal membrane of cells in the distal nephron. , 2005, American journal of physiology. Renal physiology.

[2]  K. R. Spring,et al.  Bending the MDCK Cell Primary Cilium Increases Intracellular Calcium , 2001, The Journal of Membrane Biology.

[3]  N. Hirokawa,et al.  Abnormal nodal flow precedes situs inversus in iv and inv mice. , 1999, Molecular cell.

[4]  J. Thode The calcium ion activity and the standardized excretion rate of calcium in urine of healthy adults. , 1985, Scandinavian journal of clinical and laboratory investigation.

[5]  Maurice J. Kernan,et al.  A Flagellar Polycystin-2 Homolog Required for Male Fertility in Drosophila , 2003, Current Biology.

[6]  S. Somlo,et al.  Polycystin-2 is an intracellular calcium release channel , 2002, Nature Cell Biology.

[7]  P. Davies,et al.  Flow modulation of agonist (ATP)-response (Ca2+) coupling in vascular endothelial cells. , 1991, The American journal of physiology.

[8]  W. Stehbens Turbulence of blood flow. , 1959, Quarterly journal of experimental physiology and cognate medical sciences.

[9]  D. Mekahli,et al.  Polycystin-1 and polycystin-2 are both required to amplify inositol-trisphosphate-induced Ca2+ release. , 2012, Cell calcium.

[10]  Jing Zhou,et al.  Endothelial Cilia Are Fluid Shear Sensors That Regulate Calcium Signaling and Nitric Oxide Production Through Polycystin-1 , 2008, Circulation.

[11]  Shuhei Chiba,et al.  Genetically encoded calcium indicator illuminates calcium dynamics in primary cilia , 2013, Nature Methods.

[12]  J. Verlander,et al.  Structure and function of the inner medullary collecting duct. , 1988, Kidney international.

[13]  Jing Zhou,et al.  Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells , 2003, Nature Genetics.

[14]  H. Brismar,et al.  Mechanical properties of primary cilia regulate the response to fluid flow. , 2010, American journal of physiology. Renal physiology.

[15]  T. Feldkamp,et al.  Kidney Injury Molecule-1 (KIM-1) , 2009, Der Nephrologe.

[16]  B. Dworniczak,et al.  The Ion Channel Polycystin-2 Is Required for Left-Right Axis Determination in Mice , 2002, Current Biology.

[17]  A. Resnick Chronic Fluid Flow Is an Environmental Modifier of Renal Epithelial Function , 2011, PloS one.

[18]  R. Nitschke,et al.  Flow modulates centriole movements in tubular epithelial cells , 2008, Pflügers Archiv - European Journal of Physiology.

[19]  M. Edanaga A scanning electron microscope study on the endothelium of the vessels. I. Fine structure of the endothelial surface of aorta and some other arteries in normal rabbits. , 1974, Archivum histologicum Japonicum = Nihon soshikigaku kiroku.

[20]  K. Spring,et al.  Removal of the MDCK Cell Primary Cilium Abolishes Flow Sensing , 2003, The Journal of Membrane Biology.

[21]  N. Jørgensen,et al.  Bone phenotypes of P2 receptor knockout mice. , 2011, Frontiers in bioscience.

[22]  Christopher R Jacobs,et al.  Primary cilium‐dependent mechanosensing is mediated by adenylyl cyclase 6 and cyclic AMP in bone cells , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[23]  E. A. Schwartz,et al.  Analysis and modeling of the primary cilium bending response to fluid shear. , 1997, The American journal of physiology.

[24]  Angela Wandinger-Ness,et al.  Human ADPKD primary cyst epithelial cells with a novel, single codon deletion in the PKD1 gene exhibit defective ciliary polycystin localization and loss of flow-induced Ca2+ signaling. , 2007, American journal of physiology. Renal physiology.

[25]  H. Praetorius Measuring cilium-induced Ca2+ increases in cultured renal epithelia. , 2009, Methods in cell biology.

[26]  U. Hopfer,et al.  Force-response considerations in ciliary mechanosensation. , 2007, Biophysical journal.

[27]  L. Palmer,et al.  High-conductance K channels in intercalated cells of the rat distal nephron. , 2007, American journal of physiology. Renal physiology.

[28]  L. Hocking,et al.  Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women , 2012, European Journal of Human Genetics.

[29]  R M Nerem,et al.  A mathematical model of the cytosolic-free calcium response in endothelial cells to fluid shear stress. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[30]  G. Germino,et al.  Polycystin 2 Interacts with Type I Inositol 1,4,5-Trisphosphate Receptor to Modulate Intracellular Ca2+ Signaling* , 2005, Journal of Biological Chemistry.

[31]  D. Wheatley,et al.  The centriole, a central enigma of cell biology , 1982 .

[32]  S. Murphy,et al.  ATP‐Evoked Ca2+ Mobilisation and Prostanoid Release from Astrocytes: P2‐Purinergic Receptors Linked to Phosphoinositide Hydrolysis , 1989, Journal of neurochemistry.

[33]  K. Spring,et al.  The renal cell primary cilium functions as a flow sensor. , 2003, Current opinion in nephrology and hypertension.

[34]  H. Praetorius,et al.  Released nucleotides amplify the cilium‐dependent, flow‐induced [Ca2+]i response in MDCK cells , 2009, Acta physiologica.

[35]  J. Frøkiaer,et al.  Transepithelial pressure pulses induce nucleotide release in polarized MDCK cells. , 2005, American journal of physiology. Renal physiology.

[36]  Heikki Vaananen,et al.  Primary cilia of human endothelial cells disassemble under laminar shear stress , 2004, The Journal of cell biology.

[37]  Xiangyi Lu,et al.  PKD2 Cation Channel Is Required for Directional Sperm Movement and Male Fertility , 2003, Current Biology.

[38]  R. Nitschke,et al.  Ciliary calcium signaling is modulated by kidney injury molecule-1 (Kim1) , 2007, Pflügers Archiv: European Journal of Physiology.

[39]  O. Raitakari,et al.  Flow-mediated dilatation. , 2000, British journal of clinical pharmacology.

[40]  B. Nilius,et al.  Shear stress‐induced calcium transients in endothelial cells from human umbilical cord veins. , 1992, The Journal of physiology.

[41]  P. Delmas,et al.  Shear stress-induced Ca²⁺ mobilization in MDCK cells is ATP dependent, no matter the primary cilium. , 2013, Cell calcium.

[42]  M. Edanaga A scanning electron microscope study on the endothelium of vessels. II. Fine surface structure of the endocardium in normal rabbits and rats. , 1975, Archivum histologicum Japonicum = Nihon soshikigaku kiroku.

[43]  S. Somlo,et al.  Polycystin-2 Activation by Inositol 1,4,5-Trisphosphate-induced Ca2+ Release Requires Its Direct Association with the Inositol 1,4,5-Trisphosphate Receptor in a Signaling Microdomain* , 2010, The Journal of Biological Chemistry.

[44]  J. Pácha,et al.  Apical maxi K channels in intercalated cells of CCT. , 1991, The American journal of physiology.

[45]  P. Dagnelie,et al.  Association of P2X7 receptor polymorphisms with bone mineral density and osteoporosis risk in a cohort of Dutch fracture patients , 2012, Osteoporosis International.

[46]  J. Shah,et al.  Cilioplasm is a cellular compartment for calcium signaling in response to mechanical and chemical stimuli , 2013, Cellular and Molecular Life Sciences.

[47]  Wen Liu,et al.  Ca2+ dependence of flow-stimulated K secretion in the mammalian cortical collecting duct. , 2007, American journal of physiology. Renal physiology.

[48]  K. Porter,et al.  A scanning electron microscopic study of the nephron. , 1974, The American journal of anatomy.

[49]  Michael Liebling,et al.  Endothelial cilia mediate low flow sensing during zebrafish vascular development. , 2014, Cell reports.

[50]  A. B. Maunsbach,et al.  CILIA IN DIFFERENT SEGMENTS OF THE RAT NEPHRON , 1961, The Journal of biophysical and biochemical cytology.

[51]  B. Durand,et al.  Two rotating cilia in the node cavity are sufficient to break left–right symmetry in the mouse embryo , 2012, Nature Communications.

[52]  P. Hansson,et al.  A thin-section and freeze-fracture study of the pulp blood vessels in feline and human teeth. , 1984, Archives of oral biology.

[53]  C. Naus,et al.  Connexins regulate calcium signaling by controlling ATP release. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[54]  T. Takano,et al.  Intercellular calcium signaling mediated by point-source burst release of ATP , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Yi Duan,et al.  Mechanoregulation of intracellular Ca2+ concentration is attenuated in collecting duct of monocilium-impaired orpk mice. , 2005, American journal of physiology. Renal physiology.

[56]  R. Swanson,et al.  ATP‐induced ATP release from astrocytes , 2003, Journal of neurochemistry.

[57]  J. Nakai,et al.  Cilia at the Node of Mouse Embryos Sense Fluid Flow for Left-Right Determination via Pkd2 , 2012, Science.

[58]  B. Schmidt-nielsen,et al.  Changes in fluid compartments in hamster renal papilla due to peristalsis in the pelvic wall. , 1982, Kidney international.

[59]  A. Resnick Use of optical tweezers to probe epithelial mechanosensation. , 2010, Journal of biomedical optics.

[60]  L. Guay-Woodford,et al.  Loss of primary cilia results in deregulated and unabated apical calcium entry in ARPKD collecting duct cells. , 2006, American journal of physiology. Renal physiology.

[61]  N. Hirokawa,et al.  Left-Right Asymmetry and Kinesin Superfamily Protein KIF3A: New Insights in Determination of Laterality and Mesoderm Induction by kif3A− /− Mice Analysis , 1999, The Journal of cell biology.

[62]  M. Brueckner,et al.  Two Populations of Node Monocilia Initiate Left-Right Asymmetry in the Mouse , 2003, Cell.

[63]  T. Takamatsu,et al.  Primary cilia of inv/inv mouse renal epithelial cells sense physiological fluid flow: bending of primary cilia and Ca2+ influx. , 2005, Cell structure and function.

[64]  H. Praetorius,et al.  Flow-induced [Ca2+]i increase depends on nucleotide release and subsequent purinergic signaling in the intact nephron. , 2007, Journal of the American Society of Nephrology : JASN.

[65]  K. Kosaki,et al.  27 – Genetics of Human Left-Right Axis Malformations , 1999 .

[66]  Paul W. Sternberg,et al.  A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans , 1999, Nature.

[67]  Raj Gaurav Rohatgi,et al.  Effects of luminal flow and nucleotides on [Ca(2+)](i) in rabbit cortical collecting duct. , 2002, American journal of physiology. Renal physiology.

[68]  S. Nauli,et al.  Ciliary Polycystin-2 Is a Mechanosensitive Calcium Channel Involved in Nitric Oxide Signaling Cascades , 2009, Circulation research.

[69]  Kim Van der Heiden,et al.  Primary cilia sensitize endothelial cells for fluid shear stress , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[70]  K. McCarthy,et al.  Stimulation of the P2Y Purinergic Receptor on Type 1 Astroglia Results in Inositol Phosphate Formation and Calcium Mobilization , 1992, Journal of neurochemistry.

[71]  H. Cantiello,et al.  Characterization of Single Channel Currents from Primary Cilia of Renal Epithelial Cells* , 2005, Journal of Biological Chemistry.

[72]  G. Pazour,et al.  Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease , 2002, Current Biology.

[73]  D. Clapham,et al.  Primary cilia are specialized calcium signaling organelles , 2013, Nature.

[74]  R. Thibaut-Vercruyssen,et al.  Ciliation of bovine aortic endothelial cells in culture. , 1994, Atherosclerosis.

[75]  B. Yoder,et al.  Loss of apical monocilia on collecting duct principal cells impairs ATP secretion across the apical cell surface and ATP-dependent and flow-induced calcium signals , 2007, Purinergic Signalling.

[76]  B. Schmidt-nielsen,et al.  The renal pelvis: machinery that concentrates urine in the papilla. , 2003, News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society.

[77]  F. S. Wright,et al.  Luminal calcium regulates potassium transport by the renal distal tubule. , 1990, The American journal of physiology.

[78]  O. Piro,et al.  Fluid-dynamical basis of the embryonic development of left-right asymmetry in vertebrates. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[79]  N. Pastor-Soler,et al.  Effect of aldosterone on BK channel expression in mammalian cortical collecting duct. , 2008, American journal of physiology. Renal physiology.

[80]  O. Weisz,et al.  Shear stress-dependent regulation of apical endocytosis in renal proximal tubule cells mediated by primary cilia , 2014, Proceedings of the National Academy of Sciences.

[81]  W. Lederer,et al.  Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. , 1993, Science.

[82]  B. Nilius,et al.  Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels , 2003, Nature.

[83]  '. BJORNA.AFZELIUS Situs inversus and ciliary abnormalities What is the connection ? , 2007 .

[84]  K. Willecke,et al.  Connexin 30 deficiency impairs renal tubular ATP release and pressure natriuresis. , 2009, Journal of the American Society of Nephrology : JASN.

[85]  D. Wheatley Primary cilia in normal and pathological tissues. , 1995, Pathobiology : journal of immunopathology, molecular and cellular biology.

[86]  R. Zeigel On the occurrence of cilia in several cell types of the chick pancreas. , 1962, Journal of ultrastructure research.

[87]  N. Jørgensen,et al.  Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures , 2012, European Journal of Human Genetics.

[88]  Nicholas F LaRusso,et al.  Cholangiocyte cilia detect changes in luminal fluid flow and transmit them into intracellular Ca2+ and cAMP signaling. , 2006, Gastroenterology.

[89]  C F Dewey,et al.  Fluid shear stress modulates cytosolic free calcium in vascular endothelial cells. , 1992, The American journal of physiology.

[90]  H N Sabbah,et al.  Turbulent Blood Flow in the Ascending Aorta of Humans with Normal and Diseased Aortic Valves , 1976, Circulation research.

[91]  R. F. Rushmer,et al.  Eddy Formation and Turbulence in Flowing Liquids , 1963 .

[92]  M. Brueckner,et al.  Cilia are at the heart of vertebrate left-right asymmetry. , 2003, Current opinion in genetics & development.

[93]  S. S. Árnadóttir,et al.  Renal epithelial cells can release ATP by vesicular fusion , 2013, Front. Physiol..

[94]  Jing Zhou,et al.  Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. , 2006, Journal of the American Society of Nephrology : JASN.

[95]  G. Baroudi,et al.  Differential modulation of unapposed connexin 43 hemichannel electrical conductance by protein kinase C isoforms , 2008, Pflügers Archiv - European Journal of Physiology.

[96]  D. Clapham,et al.  Direct recording and molecular identification of the calcium channel of primary cilia , 2013, Nature.

[97]  B. Yoder,et al.  Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia. , 2001, Molecular biology of the cell.

[98]  Vera Rogiers,et al.  Ca(2+) regulation of connexin 43 hemichannels in C6 glioma and glial cells. , 2009, Cell calcium.

[99]  T. Abe,et al.  Asymmetric distribution of dynamic calcium signals in the node of mouse embryo during left-right axis formation. , 2013, Developmental biology.

[100]  L. Guay-Woodford,et al.  The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. , 2002, Journal of the American Society of Nephrology : JASN.

[101]  Angela Wandinger-Ness,et al.  Attenuated, flow-induced ATP release contributes to absence of flow-sensitive, purinergic Cai2+ signaling in human ADPKD cyst epithelial cells. , 2009, American journal of physiology. Renal physiology.

[102]  Göran Stemme,et al.  Microfluidic devices for studies of primary cilium mediated cellular response to dynamic flow conditions , 2008, Biomedical microdevices.

[103]  D. Hall,et al.  The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway , 2001, Current Biology.

[104]  R. Nerem,et al.  Flow-induced calcium transients in single endothelial cells: spatial and temporal analysis. , 1992, The American journal of physiology.

[105]  M. Edanaga A Scanning Electron Microscope Study on the Endothelium of the Vessels , 1974 .

[106]  K. Kosaki,et al.  Genetics of human left-right axis malformations. , 1998, Seminars in cell & developmental biology.

[107]  W. Pfaller,et al.  A critical reevaluation of the structure of the rat uriniferous tubule as revealed by scanning electron microscopy , 1976, Cell and Tissue Research.

[108]  J. Ando,et al.  Cytoplasmic calcium response to fluid shear stress in cultured vascular endothelial cells , 1988, In Vitro Cellular & Developmental Biology.