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Search Results: 1 - 10 of 264784 matches for " Didier Y. R. Stainier "
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Lessons from “Lower” Organisms: What Worms, Flies, and Zebrafish Can Teach Us about Human Energy Metabolism
Amnon Schlegel ,Didier Y. R Stainier
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030199
Abstract: A pandemic of metabolic diseases (atherosclerosis, diabetes mellitus, and obesity), unleashed by multiple social and economic factors beyond the control of most individuals, threatens to diminish human life span for the first time in the modern era. Given the redundancy and inherent complexity of processes regulating the uptake, transport, catabolism, and synthesis of nutrients, magic bullets to target these diseases will be hard to find. Recent studies using the worm Caenorhabditis elegans, the fly Drosophila melanogaster, and the zebrafish Danio rerio indicate that these “lower” metazoans possess unique attributes that should help in identifying, investigating, and even validating new pharmaceutical targets for these diseases. We summarize findings in these organisms that shed light on highly conserved pathways of energy homeostasis.
Hepatocyte Growth Factor Signaling in Intrapancreatic Ductal Cells Drives Pancreatic Morphogenesis
Ryan M. Anderson ,Marion Delous,Justin A. Bosch,Lihua Ye,Morgan A. Robertson,Daniel Hesselson,Didier Y. R. Stainier
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003650
Abstract: In a forward genetic screen for regulators of pancreas development in zebrafish, we identified donuts908, a mutant which exhibits failed outgrowth of the exocrine pancreas. The s908 mutation leads to a leucine to arginine substitution in the ectodomain of the hepatocyte growth factor (HGF) tyrosine kinase receptor, Met. This missense mutation impedes the proteolytic maturation of the receptor, its trafficking to the plasma membrane, and diminishes the phospho-activation of its kinase domain. Interestingly, during pancreatogenesis, met and its hgf ligands are expressed in pancreatic epithelia and mesenchyme, respectively. Although Met signaling elicits mitogenic and migratory responses in varied contexts, normal proliferation rates in donut mutant pancreata together with dysmorphic, mislocalized ductal cells suggest that met primarily functions motogenically in pancreatic tail formation. Treatment with PI3K and STAT3 inhibitors, but not with MAPK inhibitors, phenocopies the donut pancreatic defect, further indicating that Met signals through migratory pathways during pancreas development. Chimera analyses showed that Met-deficient cells were excluded from the duct, but not acinar, compartment in the pancreatic tail. Conversely, wild-type intrapancreatic duct and “tip cells” at the leading edge of the growing pancreas rescued the donut phenotype. Altogether, these results reveal a novel and essential role for HGF signaling in the intrapancreatic ducts during exocrine morphogenesis.
Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish
Thomas Bartman,Emily C. Walsh,Kuo-Kuang Wen,Melissa McKane,Jihui Ren,Jonathan Alexander,Peter A. Rubenstein,Didier Y. R. Stainier
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0020129
Abstract: Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih?/?) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk?/?) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk?/? embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfks11 variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease.
Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish
Thomas Bartman,Emily C Walsh,Kuo-Kuang Wen,Melissa McKane,Jihui Ren,Jonathan Alexander,Peter A Rubenstein,Didier Y. R Stainier
PLOS Biology , 2004, DOI: 10.1371/journal.pbio.0020129
Abstract: Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih?/?) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk?/?) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk?/? embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfks11 variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease.
Genetic and Physiologic Dissection of the Vertebrate Cardiac Conduction System
Neil C. Chi,Robin M. Shaw,Benno Jungblut,Jan Huisken,Tania Ferrer,Rima Arnaout,Ian Scott,Dimitris Beis,Tong Xiao,Herwig Baier,Lily Y. Jan,Martin Tristani-Firouzi,Didier Y. R. Stainier
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0060109
Abstract: Vertebrate hearts depend on highly specialized cardiomyocytes that form the cardiac conduction system (CCS) to coordinate chamber contraction and drive blood efficiently and unidirectionally throughout the organism. Defects in this specialized wiring system can lead to syncope and sudden cardiac death. Thus, a greater understanding of cardiac conduction development may help to prevent these devastating clinical outcomes. Utilizing a cardiac-specific fluorescent calcium indicator zebrafish transgenic line, Tg(cmlc2:gCaMP)s878, that allows for in vivo optical mapping analysis in intact animals, we identified and analyzed four distinct stages of cardiac conduction development that correspond to cellular and anatomical changes of the developing heart. Additionally, we observed that epigenetic factors, such as hemodynamic flow and contraction, regulate the fast conduction network of this specialized electrical system. To identify novel regulators of the CCS, we designed and performed a new, physiology-based, forward genetic screen and identified for the first time, to our knowledge, 17 conduction-specific mutations. Positional cloning of hobgoblins634 revealed that tcf2, a homeobox transcription factor gene involved in mature onset diabetes of the young and familial glomerulocystic kidney disease, also regulates conduction between the atrium and the ventricle. The combination of the Tg(cmlc2:gCaMP)s878 line/in vivo optical mapping technique and characterization of cardiac conduction mutants provides a novel multidisciplinary approach to further understand the molecular determinants of the vertebrate CCS.
Genetic and Physiologic Dissection of the Vertebrate Cardiac Conduction System
Neil C Chi ,Robin M Shaw,Benno Jungblut,Jan Huisken,Tania Ferrer,Rima Arnaout,Ian Scott,Dimitris Beis,Tong Xiao,Herwig Baier,Lily Y Jan,Martin Tristani-Firouzi,Didier Y. R Stainier
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.0060109
Abstract: Vertebrate hearts depend on highly specialized cardiomyocytes that form the cardiac conduction system (CCS) to coordinate chamber contraction and drive blood efficiently and unidirectionally throughout the organism. Defects in this specialized wiring system can lead to syncope and sudden cardiac death. Thus, a greater understanding of cardiac conduction development may help to prevent these devastating clinical outcomes. Utilizing a cardiac-specific fluorescent calcium indicator zebrafish transgenic line, Tg(cmlc2:gCaMP)s878, that allows for in vivo optical mapping analysis in intact animals, we identified and analyzed four distinct stages of cardiac conduction development that correspond to cellular and anatomical changes of the developing heart. Additionally, we observed that epigenetic factors, such as hemodynamic flow and contraction, regulate the fast conduction network of this specialized electrical system. To identify novel regulators of the CCS, we designed and performed a new, physiology-based, forward genetic screen and identified for the first time, to our knowledge, 17 conduction-specific mutations. Positional cloning of hobgoblins634 revealed that tcf2, a homeobox transcription factor gene involved in mature onset diabetes of the young and familial glomerulocystic kidney disease, also regulates conduction between the atrium and the ventricle. The combination of the Tg(cmlc2:gCaMP)s878 line/in vivo optical mapping technique and characterization of cardiac conduction mutants provides a novel multidisciplinary approach to further understand the molecular determinants of the vertebrate CCS.
sox9b Is a Key Regulator of Pancreaticobiliary Ductal System Development
Marion Delous equal contributor ,Chunyue Yin equal contributor,Donghun Shin,Nikolay Ninov,Juliana Debrito Carten,Luyuan Pan,Taylur P. Ma,Steven A. Farber,Cecilia B. Moens,Didier Y. R. Stainier
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002754
Abstract: The pancreaticobiliary ductal system connects the liver and pancreas to the intestine. It is composed of the hepatopancreatic ductal (HPD) system as well as the intrahepatic biliary ducts and the intrapancreatic ducts. Despite its physiological importance, the development of the pancreaticobiliary ductal system remains poorly understood. The SRY-related transcription factor SOX9 is expressed in the mammalian pancreaticobiliary ductal system, but the perinatal lethality of Sox9 heterozygous mice makes loss-of-function analyses challenging. We turned to the zebrafish to assess the role of SOX9 in pancreaticobiliary ductal system development. We first show that zebrafish sox9b recapitulates the expression pattern of mouse Sox9 in the pancreaticobiliary ductal system and use a nonsense allele of sox9b, sox9bfh313, to dissect its function in the morphogenesis of this structure. Strikingly, sox9bfh313 homozygous mutants survive to adulthood and exhibit cholestasis associated with hepatic and pancreatic duct proliferation, cyst formation, and fibrosis. Analysis of sox9bfh313 mutant embryos and larvae reveals that the HPD cells appear to mis-differentiate towards hepatic and/or pancreatic fates, resulting in a dysmorphic structure. The intrahepatic biliary cells are specified but fail to assemble into a functional network. Similarly, intrapancreatic duct formation is severely impaired in sox9bfh313 mutants, while the embryonic endocrine and acinar compartments appear unaffected. The defects in the intrahepatic and intrapancreatic ducts of sox9bfh313 mutants worsen during larval and juvenile stages, prompting the adult phenotype. We further show that Sox9b interacts with Notch signaling to regulate intrahepatic biliary network formation: sox9b expression is positively regulated by Notch signaling, while Sox9b function is required to maintain Notch signaling in the intrahepatic biliary cells. Together, these data reveal key roles for SOX9 in the morphogenesis of the pancreaticobiliary ductal system, and they cast human Sox9 as a candidate gene for pancreaticobiliary duct malformation-related pathologies.
Autophagy Induction Is a Tor- and Tp53-Independent Cell Survival Response in a Zebrafish Model of Disrupted Ribosome Biogenesis
Yeliz Boglev,Andrew P. Badrock,Andrew J. Trotter,Qian Du,Elsbeth J. Richardson,Adam C. Parslow,Sebastian J. Markmiller,Nathan E. Hall,Tanya A. de Jong-Curtain,Annie Y. Ng,Heather Verkade,Elke A. Ober,Holly A. Field,Donghun Shin,Chong H. Shin,Katherine M. Hannan,Ross D. Hannan,Richard B. Pearson,Seok-Hyung Kim,Kevin C. Ess,Graham J. Lieschke,Didier Y. R. Stainier,Joan K. Heath
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003279
Abstract: Ribosome biogenesis underpins cell growth and division. Disruptions in ribosome biogenesis and translation initiation are deleterious to development and underlie a spectrum of diseases known collectively as ribosomopathies. Here, we describe a novel zebrafish mutant, titania (ttis450), which harbours a recessive lethal mutation in pwp2h, a gene encoding a protein component of the small subunit processome. The biochemical impacts of this lesion are decreased production of mature 18S rRNA molecules, activation of Tp53, and impaired ribosome biogenesis. In ttis450, the growth of the endodermal organs, eyes, brain, and craniofacial structures is severely arrested and autophagy is up-regulated, allowing intestinal epithelial cells to evade cell death. Inhibiting autophagy in ttis450 larvae markedly reduces their lifespan. Somewhat surprisingly, autophagy induction in ttis450 larvae is independent of the state of the Tor pathway and proceeds unabated in Tp53-mutant larvae. These data demonstrate that autophagy is a survival mechanism invoked in response to ribosomal stress. This response may be of relevance to therapeutic strategies aimed at killing cancer cells by targeting ribosome biogenesis. In certain contexts, these treatments may promote autophagy and contribute to cancer cells evading cell death.
Vertebrate Hedgehog signaling: cilia rule
Christopher W Wilson, Didier YR Stainier
BMC Biology , 2010, DOI: 10.1186/1741-7007-8-102
Abstract: See research article: http://www.biomedcentral.com/1741-7007/8/65 webciteHedgehog (Hh) signaling is an evolutionarily conserved signal transduction pathway that is essential for a range of developmental patterning events, including specifying growth and polarity of the vertebrate limb and neural tube, and is misregulated in a number of cancers, for example basal cell carcinoma and medulloblastoma [1]. It has recently become clear that the primary cilium (Figure 1a), a non-motile microtubule-based structure that extends from membrane-docked basal bodies in most mammalian cell types, is essential for Hh signaling in the mouse, but not in the fruit fly Drosophila melanogaster [2]. Subsequent experiments with null mutants in components of the Hh pathway in zebrafish and mouse have raised questions about the conservation of the mechanisms of Hh signal transuction during evolution, and have suggested that utilization of the primary cilium for signaling might be a mammalian innovation. Now, data from several groups, including Kim et al. in BMC Biology [3], show that cilia are required for Hh signaling in zebrafish, revealing that their deployment in this pathway is thus not confined to mammals. Further, the studies demonstrate that the iguana gene product, originally implicated in the regulation of Hh signaling in zebrafish, has in fact a conserved role in ciliogenesis.Most of the important components of the Hh signal transduction pathway have been known for some time to be conserved from invertebrates to vertebrates [1]. The function of Hh is to regulate the activity of Gli-family transcriptional regulators (Ci in Drosophila, Gli in vertebrates). In the absence of Hh signaling, Ci/Gli transcriptional regulators undergo proteasome-dependent limited proteolysis to a truncated form in which they act as transcriptional repressors, a process that also requires the scaffolding protein Costal-2/Kinesin family member 7 (Cos-2/Kif7). Hh signaling causes Ci/Gli proteins instead to
Probing the limits of regional tissue oxygenation measures
Michael R Pinsky, Didier Payen
Critical Care , 2009, DOI: 10.1186/cc7999
Abstract: Presently, there are neither generally accepted measures of global tissue viability nor reasonable leading candidate measures on the horizon. For example, although the strong ion gap assessment of metabolic acidosis predicts mortality in trauma patients, it cannot be used to assess response to therapy because crystalloid resuscitation itself alters the strong ion gap [1]. Furthermore, although regional measures of metabolism such as the sublingual tissue partial pressure of carbon dioxide [2] and urethral mucosal NAD/NADH ratios [3] track circulatory deficiency and resuscitation, their ability to assess the global status and their intrinsically highly unstable baseline values make their routine clinical use limited.Non-invasive continuous measurements of tissue hemoglobin oxygenation using near-infrared spectroscopy have been studied and proposed to assess tissue hypoperfusion. The absolute tissue oxygen saturation (StO2) has been proven to be instrumental in predicting outcome in trauma patients [4] but is otherwise relatively insensitive to define earlier stages of tissue hypoperfusion, despite adequate macrocirculation resuscitation aiming to prevent ischemic organ injury. The use of continuous StO2 as a marker of tissue perfusion is still being studied, however, and potentially may demonstrate greater sensitivity early on in trauma resuscitation.Increased interest in functional hemodynamic monitoring [5], for which the fluid challenge or exercise stress test are classic examples, has recently been applied since observed static numbers cannot really evaluate the adequacy of tissue perfusion, especially regional measures of blood flow and tissue viability. Although systemic hypotension with hypoperfusion, a low mixed venous oxygen saturation and elevated serum lactate levels may be used to identify tissue ischemia, normal blood pressure, flow rates, mixed venous oxygen saturation and lactate levels do not ensure the adequacy of resuscitation. In this regard, the u
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