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Search Results: 1 - 10 of 463011 matches for " Iain A. Drummond "
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Mechanical Stretch and PI3K Signaling Link Cell Migration and Proliferation to Coordinate Epithelial Tubule Morphogenesis in the Zebrafish Pronephros
Aleksandr Vasilyev, Yan Liu, Nathan Hellman, Narendra Pathak, Iain A. Drummond
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039992
Abstract: Organ development leads to the emergence of organ function, which in turn can impact developmental processes. Here we show that fluid flow-induced collective epithelial migration during kidney nephron morphogenesis induces cell stretch that in turn signals epithelial proliferation. Increased cell proliferation was dependent on PI3K signaling. Inhibiting epithelial proliferation by blocking PI3K or CDK4/Cyclin D1 activity arrested cell migration prematurely and caused a marked overstretching of the distal nephron tubule. Computational modeling of the involved cell processes predicted major morphological and kinetic outcomes observed experimentally under a variety of conditions. Overall, our findings suggest that kidney development is a recursive process where emerging organ function “feeds back” to the developmental program to influence fundamental cellular events such as cell migration and proliferation, thus defining final organ morphology.
The Lowe Syndrome Protein OCRL1 Is Required for Endocytosis in the Zebrafish Pronephric Tubule
Francesca Oltrabella?,Grzegorz Pietka?,Irene Barinaga-Rementeria Ramirez?,Aleksandr Mironov?,Toby Starborg?,Iain A. Drummond,Katherine A. Hinchliffe?,Martin Lowe
PLOS Genetics , 2015, DOI: 10.1371/journal.pgen.1005058
Abstract: Lowe syndrome and Dent-2 disease are caused by mutation of the inositol 5-phosphatase OCRL1. Despite our increased understanding of the cellular functions of OCRL1, the underlying basis for the renal tubulopathy seen in both human disorders, of which a hallmark is low molecular weight proteinuria, is currently unknown. Here, we show that deficiency in OCRL1 causes a defect in endocytosis in the zebrafish pronephric tubule, a model for the mammalian renal tubule. This coincides with a reduction in levels of the scavenger receptor megalin and its accumulation in endocytic compartments, consistent with reduced recycling within the endocytic pathway. We also observe reduced numbers of early endocytic compartments and enlarged vacuolar endosomes in the sub-apical region of pronephric cells. Cell polarity within the pronephric tubule is unaffected in mutant embryos. The OCRL1-deficient embryos exhibit a mild ciliogenesis defect, but this cannot account for the observed impairment of endocytosis. Catalytic activity of OCRL1 is required for renal tubular endocytosis and the endocytic defect can be rescued by suppression of PIP5K. These results indicate for the first time that OCRL1 is required for endocytic trafficking in vivo, and strongly support the hypothesis that endocytic defects are responsible for the renal tubulopathy in Lowe syndrome and Dent-2 disease. Moreover, our results reveal PIP5K as a potential therapeutic target for Lowe syndrome and Dent-2 disease.
Collective Cell Migration Drives Morphogenesis of the Kidney Nephron
Aleksandr Vasilyev,Yan Liu,Sudha Mudumana,Steve Mangos,Pui-Ying Lam,Arindam Majumdar,Jinhua Zhao,Kar-Lai Poon,Igor Kondrychyn,Vladimir Korzh,Iain A. Drummond
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000009
Abstract: Tissue organization in epithelial organs is achieved during development by the combined processes of cell differentiation and morphogenetic cell movements. In the kidney, the nephron is the functional organ unit. Each nephron is an epithelial tubule that is subdivided into discrete segments with specific transport functions. Little is known about how nephron segments are defined or how segments acquire their distinctive morphology and cell shape. Using live, in vivo cell imaging of the forming zebrafish pronephric nephron, we found that the migration of fully differentiated epithelial cells accounts for both the final position of nephron segment boundaries and the characteristic convolution of the proximal tubule. Pronephric cells maintain adherens junctions and polarized apical brush border membranes while they migrate collectively. Individual tubule cells exhibit basal membrane protrusions in the direction of movement and appear to establish transient, phosphorylated Focal Adhesion Kinase–positive adhesions to the basement membrane. Cell migration continued in the presence of camptothecin, indicating that cell division does not drive migration. Lengthening of the nephron was, however, accompanied by an increase in tubule cell number, specifically in the most distal, ret1-positive nephron segment. The initiation of cell migration coincided with the onset of fluid flow in the pronephros. Complete blockade of pronephric fluid flow prevented cell migration and proximal nephron convolution. Selective blockade of proximal, filtration-driven fluid flow shifted the position of tubule convolution distally and revealed a role for cilia-driven fluid flow in persistent migration of distal nephron cells. We conclude that nephron morphogenesis is driven by fluid flow–dependent, collective epithelial cell migration within the confines of the tubule basement membrane. Our results establish intimate links between nephron function, fluid flow, and morphogenesis.
Collective Cell Migration Drives Morphogenesis of the Kidney Nephron
Aleksandr Vasilyev,Yan Liu,Sudha Mudumana,Steve Mangos,Pui-Ying Lam,Arindam Majumdar,Jinhua Zhao,Kar-Lai Poon,Igor Kondrychyn,Vladimir Korzh,Iain A Drummond
PLOS Biology , 2009, DOI: 10.1371/journal.pbio.1000009
Abstract: Tissue organization in epithelial organs is achieved during development by the combined processes of cell differentiation and morphogenetic cell movements. In the kidney, the nephron is the functional organ unit. Each nephron is an epithelial tubule that is subdivided into discrete segments with specific transport functions. Little is known about how nephron segments are defined or how segments acquire their distinctive morphology and cell shape. Using live, in vivo cell imaging of the forming zebrafish pronephric nephron, we found that the migration of fully differentiated epithelial cells accounts for both the final position of nephron segment boundaries and the characteristic convolution of the proximal tubule. Pronephric cells maintain adherens junctions and polarized apical brush border membranes while they migrate collectively. Individual tubule cells exhibit basal membrane protrusions in the direction of movement and appear to establish transient, phosphorylated Focal Adhesion Kinase–positive adhesions to the basement membrane. Cell migration continued in the presence of camptothecin, indicating that cell division does not drive migration. Lengthening of the nephron was, however, accompanied by an increase in tubule cell number, specifically in the most distal, ret1-positive nephron segment. The initiation of cell migration coincided with the onset of fluid flow in the pronephros. Complete blockade of pronephric fluid flow prevented cell migration and proximal nephron convolution. Selective blockade of proximal, filtration-driven fluid flow shifted the position of tubule convolution distally and revealed a role for cilia-driven fluid flow in persistent migration of distal nephron cells. We conclude that nephron morphogenesis is driven by fluid flow–dependent, collective epithelial cell migration within the confines of the tubule basement membrane. Our results establish intimate links between nephron function, fluid flow, and morphogenesis.
Collective Epithelial Migration Drives Kidney Repair after Acute Injury
Aurélien Palmyre, Jeongeun Lee, Gennadiy Ryklin, Troy Camarata, Martin K. Selig, Anne-Laure Duchemin, Paul Nowak, M. Amin Arnaout, Iain A. Drummond, Aleksandr Vasilyev
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101304
Abstract: Acute kidney injury (AKI) is a common and significant medical problem. Despite the kidney’s remarkable regenerative capacity, the mortality rate for the AKI patients is high. Thus, there remains a need to better understand the cellular mechanisms of nephron repair in order to develop new strategies that would enhance the intrinsic ability of kidney tissue to regenerate. Here, using a novel, laser ablation-based, zebrafish model of AKI, we show that collective migration of kidney epithelial cells is a primary early response to acute injury. We also show that cell proliferation is a late response of regenerating kidney epithelia that follows cell migration during kidney repair. We propose a computational model that predicts this temporal relationship and suggests that cell stretch is a mechanical link between migration and proliferation, and present experimental evidence in support of this hypothesis. Overall, this study advances our understanding of kidney repair mechanisms by highlighting a primary role for collective cell migration, laying a foundation for new approaches to treatment of AKI.
Zoological Catalogue of Australia Vol. 33 Echinodermata/F.W.E. Rowe & J. Gates
A. Drummond
African Zoology , 2011,
Abstract: The Zoological Catalogue of Australia is a remarkable series of some 90 volumes, each covering a specific animal group and citing by name and original reference all species known from Australia. This series aims to serve as a directory to the most recent information available on each species in the Australian fauna.
Exposure to wave action: some consequences for the sea urchin Stomopneustes variolaris on the Natal coast
A.E. Drummond
African Zoology , 2012,
Abstract: ENGLISH ABSTRACT: Population size structure in the intertidal echinoid, Stomopneustes variolaris, has been observed to vary between habitats, in a manner which suggests the influence of factors in addition to variation in recruitment success. This paper reports on an investigation into the hypothesis that exposure to wave action might be a factor accounting for the variation in population size structure between habitats at Sheffield Beach. *********** AFRIKAANSE OPSOMMING: Populasiegroottestruktuur in die tussengety echinoidea, Stomopneustes variolaris varieer tussen habitatte op 'n wyse wat die invloed van faktore bUlte en behalwe 'n variasie In aanwerwingsukses aandui. In hierdie artikel word die hipotese ondersoek dat blootsteiling aan golfaksie 'n moontlike faktor kan wees in die variasie in populasiegroottestruktuur tussen die Sheffieldstrandhabitatte.
βENaC is a molecular component of a VSMC mechanotransducer that contributes to renal blood flow regulation, protection from renal injury, and hypertension
Heather A. Drummond
Frontiers in Physiology , 2012, DOI: 10.3389/fphys.2012.00341
Abstract: Pressure-induced constriction (also known as the “myogenic response”) is an important mechano-dependent response in certain blood vessels. The response is mediated by vascular smooth muscle cells (VSMCs) and characterized by a pressure-induced vasoconstriction in small arteries and arterioles in the cerebral, mesenteric, cardiac, and renal beds. The myogenic response has two important roles; it is a mechanism of blood flow autoregulation and provides protection against systemic blood pressure-induced damage to delicate microvessels. However, the molecular mechanism(s) underlying initiation of myogenic response is unclear. Degenerin proteins have a strong evolutionary link to mechanotransduction in the nematode. Our laboratory has addressed the hypothesis that these proteins may also act as mechanosensors in certain mammalian tissues such as VSMCs and arterial baroreceptor neurons. This article discusses the importance of a specific degenerin protein, β Epithelial Na+ Channel (βENaC) in pressure-induced vasoconstriction in renal vessels and arterial baroreflex function as determined in a mouse model of reduced βENaC (βENaC m/m). We propose that loss of baroreflex sensitivity (due to loss of baroreceptor βENaC) increases blood pressure variability, increasing the likelihood and magnitude of upward swings in systemic pressure. Furthermore, loss of the myogenic constrictor response (due to loss of VSMC βENaC) will permit those pressure swings to be transmitted to the microvasculature in βENaC m/m mice, thus increasing the susceptibility to renal injury and hypertension.
Nephronophthisis-Associated CEP164 Regulates Cell Cycle Progression, Apoptosis and Epithelial-to-Mesenchymal Transition
Gisela G. Slaats,Amiya K. Ghosh equal contributor,Lucas L. Falke equal contributor,Stéphanie Le Corre,Indra A. Shaltiel,Glenn van de Hoek,Timothy D. Klasson,Marijn F. Stokman,Ive Logister,Marianne C. Verhaar,Roel Goldschmeding,Tri Q. Nguyen,Iain A. Drummond,Friedhelm Hildebrandt,Rachel H. Giles
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004594
Abstract: We recently reported that centrosomal protein 164 (CEP164) regulates both cilia and the DNA damage response in the autosomal recessive polycystic kidney disease nephronophthisis. Here we examine the functional role of CEP164 in nephronophthisis-related ciliopathies and concomitant fibrosis. Live cell imaging of RPE-FUCCI (fluorescent, ubiquitination-based cell cycle indicator) cells after siRNA knockdown of CEP164 revealed an overall quicker cell cycle than control cells, although early S-phase was significantly longer. Follow-up FACS experiments with renal IMCD3 cells confirm that Cep164 siRNA knockdown promotes cells to accumulate in S-phase. We demonstrate that this effect can be rescued by human wild-type CEP164, but not disease-associated mutants. siRNA of CEP164 revealed a proliferation defect over time, as measured by CyQuant assays. The discrepancy between accelerated cell cycle and inhibited overall proliferation could be explained by induction of apoptosis and epithelial-to-mesenchymal transition. Reduction of CEP164 levels induces apoptosis in immunofluorescence, FACS and RT-QPCR experiments. Furthermore, knockdown of Cep164 or overexpression of dominant negative mutant allele CEP164 Q525X induces epithelial-to-mesenchymal transition, and concomitant upregulation of genes associated with fibrosis. Zebrafish injected with cep164 morpholinos likewise manifest developmental abnormalities, impaired DNA damage signaling, apoptosis and a pro-fibrotic response in vivo. This study reveals a novel role for CEP164 in the pathogenesis of nephronophthisis, in which mutations cause ciliary defects coupled with DNA damage induced replicative stress, cell death, and epithelial-to-mesenchymal transition, and suggests that these events drive the characteristic fibrosis observed in nephronophthisis kidneys.
Jet Physics at the Tevatron
Iain A. Bertram
Physics , 2003,
Abstract: Results are presented from analyses of jet data produced in pbarp collisions at $\sqrt{s}$ = 1960 GeV collected with the DZero and CDF detectors during 2002--03 at the Fermilab Tevatron Collider. Preliminary measurements of the inclusive jet cross section, the dijet mass spectrum, and jet structure are presented.
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