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N-ethyl-N-nitrosourea mutagenesis produced a small number of mice with altered plasma electrolyte levels
Bernhard Aigner, Birgit Rathkolb, Martina Klempt, Sibylle Wagner, Dian Michel, Martin Hrabé de Angelis, Eckhard Wolf
Journal of Biomedical Science , 2009, DOI: 10.1186/1423-0127-16-53
Abstract: Here, we retrospectively evaluated the use of the plasma electrolytes calcium, chloride, inorganic phosphorus, potassium and sodium in the Munich ENU mouse mutagenesis project where clinical chemical blood analysis was carried out on more than 20,000 G1 and G3 offspring of chemically mutagenized inbred C3H mice to detect dominant and recessive mutations leading to deviations in various plasma parameter levels.We identified a small number of animals consistently exhibiting altered plasma electrolyte values. Transmission of the phenotypic deviations to the subsequent generations led to the successful establishment of mutant lines for the parameters calcium and potassium. Published data from other phenotype-driven ENU projects also included only a small number of mutant lines which were generated according to altered plasma electrolyte levels.Thus, use of plasma electrolytes detected few mouse mutants in ENU projects compared to other clinical chemical blood parameters.Clinical chemical plasma analyses are often used in the medical examination of patients for the diagnosis of the involvement of various organs as well as for the evaluation of therapeutic strategies in multifactorial and polygenic human diseases. Electrolytes including calcium, chloride, inorganic phosphorus, potassium and sodium are routine parameters in these analyses. The diagnostic impact of plasma electrolyte values includes the general maintenance of osmotic pressure, water distribution and acid-base equilibrium (Na, Cl, K) as well as tissue-specific metabolism and organ function, especially of bone and kidney. Comparison of intracellular versus extracellular distribution of the electrolytes reveals that K is the chief intracellular cation, therefore, measured plasma K values are increased in the case of hemolysis or cellular stress like muscle trauma (Table 1). Together with the results of other diagnostic parameters, plasma electrolytes contribute to the identification of the impaired organ funct
ER Stress-Mediated Apoptosis in a New Mouse Model of Osteogenesis imperfecta
Thomas S Lisse,Frank Thiele,Helmut Fuchs,Wolfgang Hans,Gerhard K. H Przemeck,Koichiro Abe,Birgit Rathkolb,Leticia Quintanilla-Martinez,Gabriele Hoelzlwimmer,Miep Helfrich,Eckhard Wolf,Stuart H Ralston,Martin Hrabé de Angelis
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.0040007
Abstract: Osteogenesis imperfecta is an inherited disorder characterized by increased bone fragility, fractures, and osteoporosis, and most cases are caused by mutations affecting the type I collagen genes. Here, we describe a new mouse model for Osteogenesis imperfecta termed Aga2 (abnormal gait 2) that was isolated from the Munich N-ethyl-N-nitrosourea mutagenesis program and exhibited phenotypic variability, including reduced bone mass, multiple fractures, and early lethality. The causal gene was mapped to Chromosome 11 by linkage analysis, and a C-terminal frameshift mutation was identified in the Col1a1 (procollagen type I, alpha 1) gene as the cause of the disorder. Aga2 heterozygous animals had markedly increased bone turnover and a disrupted native collagen network. Further studies showed that abnormal proα1(I) chains accumulated intracellularly in Aga2/+ dermal fibroblasts and were poorly secreted extracellularly. This was associated with the induction of an endoplasmic reticulum stress-specific unfolded protein response involving upregulation of BiP, Hsp47, and Gadd153 with caspases-12 and ?3 activation and apoptosis of osteoblasts both in vitro and in vivo. These studies resulted in the identification of a new model for Osteogenesis imperfecta, and identified a role for intracellular modulation of the endoplasmic reticulum stress-associated unfolded protein response machinery toward osteoblast apoptosis during the pathogenesis of disease.
Mechanisms Controlling Anaemia in Trypanosoma congolense Infected Mice
Harry A. Noyes, Mohammad H. Alimohammadian, Morris Agaba, Andy Brass, Helmut Fuchs, Valerie Gailus-Durner, Helen Hulme, Fuad Iraqi, Stephen Kemp, Birgit Rathkolb, Eckard Wolf, Martin Hrabé de Angelis, Delnaz Roshandel, Jan Naessens
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005170
Abstract: Background Trypanosoma congolense are extracellular protozoan parasites of the blood stream of artiodactyls and are one of the main constraints on cattle production in Africa. In cattle, anaemia is the key feature of disease and persists after parasitaemia has declined to low or undetectable levels, but treatment to clear the parasites usually resolves the anaemia. Methodology/Principal Findings The progress of anaemia after Trypanosoma congolense infection was followed in three mouse strains. Anaemia developed rapidly in all three strains until the peak of the first wave of parasitaemia. This was followed by a second phase, characterized by slower progress to severe anaemia in C57BL/6, by slow recovery in surviving A/J and a rapid recovery in BALB/c. There was no association between parasitaemia and severity of anaemia. Furthermore, functional T lymphocytes are not required for the induction of anaemia, since suppression of T cell activity with Cyclosporin A had neither an effect on the course of infection nor on anaemia. Expression of genes involved in erythropoiesis and iron metabolism was followed in spleen, liver and kidney tissues in the three strains of mice using microarrays. There was no evidence for a response to erythropoietin, consistent with anaemia of chronic disease, which is erythropoietin insensitive. However, the expression of transcription factors and genes involved in erythropoiesis and haemolysis did correlate with the expression of the inflammatory cytokines Il6 and Ifng. Conclusions/Significance The innate immune response appears to be the major contributor to the inflammation associated with anaemia since suppression of T cells with CsA had no observable effect. Several transcription factors regulating haematopoiesis, Tal1, Gata1, Zfpm1 and Klf1 were expressed at consistently lower levels in C57BL/6 mice suggesting that these mice have a lower haematopoietic capacity and therefore less ability to recover from haemolysis induced anaemia after infection.
Loss of the Actin Remodeler Eps8 Causes Intestinal Defects and Improved Metabolic Status in Mice
Arianna Tocchetti,Charlotte Blanche Ekalle Soppo,Fabio Zani,Fabrizio Bianchi,Maria Cristina Gagliani,Benedetta Pozzi,Jan Rozman,Ralf Elvert,Nicole Ehrhardt,Birgit Rathkolb,Corinna Moerth,Marion Horsch,Helmut Fuchs,Valérie Gailus-Durner,Johannes Beckers,Martin Klingenspor,Eckhard Wolf,Martin Hrabé de Angelis,Eugenio Scanziani,Carlo Tacchetti,Giorgio Scita,Pier Paolo Di Fiore,Nina Offenh?user
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009468
Abstract: In a variety of organisms, including mammals, caloric restriction improves metabolic status and lowers the incidence of chronic-degenerative diseases, ultimately leading to increased lifespan.
Dll1 Haploinsufficiency in Adult Mice Leads to a Complex Phenotype Affecting Metabolic and Immunological Processes
Isabel Rubio-Aliaga, Gerhard K. H. Przemeck, Helmut Fuchs, Valérie Gailus-Durner, Thure Adler, Wolfgang Hans, Marion Horsch, Birgit Rathkolb, Jan Rozman, Anja Schrewe, Sibylle Wagner, Sabine M. Hoelter, Lore Becker, Thomas Klopstock, Wolfgang Wurst, Eckhard Wolf, Martin Klingenspor, Boris T. Ivandic, Dirk H. Busch, Johannes Beckers, Martin Hrabé de Angelis
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006054
Abstract: Background The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1) is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage. Methodology/Principal Findings Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1C413Y). Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized. Conclusions/Significance In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes.
The Endocytic Adaptor Eps15 Controls Marginal Zone B Cell Numbers
Benedetta Pozzi, Stefania Amodio, Caterina Lucano, Anna Sciullo, Simona Ronzoni, Daniela Castelletti, Thure Adler, Irina Treise, Ingrid Holmberg Betsholtz, Birgit Rathkolb, Dirk H. Busch, Eckhard Wolf, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabě de Angelis, Christer Betsholtz, Stefano Casola, Pier Paolo Di Fiore, Nina Offenh?user
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050818
Abstract: Eps15 is an endocytic adaptor protein involved in clathrin and non-clathrin mediated endocytosis. In Caenorhabditis elegans and Drosophila melanogaster lack of Eps15 leads to defects in synaptic vesicle recycling and synapse formation. We generated Eps15-KO mice to investigate its function in mammals. Eps15-KO mice are born at the expected Mendelian ratio and are fertile. Using a large-scale phenotype screen covering more than 300 parameters correlated to human disease, we found that Eps15-KO mice did not show any sign of disease or neural deficits. Instead, altered blood parameters pointed to an immunological defect. By competitive bone marrow transplantation we demonstrated that Eps15-KO hematopoietic precursor cells were more efficient than the WT counterparts in repopulating B220+ bone marrow cells, CD19? thymocytes and splenic marginal zone (MZ) B cells. Eps15-KO mice showed a 2-fold increase in MZ B cell numbers when compared with controls. Using reverse bone marrow transplantation, we found that Eps15 regulates MZ B cell numbers in a cell autonomous manner. FACS analysis showed that although MZ B cells were increased in Eps15-KO mice, transitional and pre-MZ B cell numbers were unaffected. The increase in MZ B cell numbers in Eps15 KO mice was not dependent on altered BCR signaling or Notch activity. In conclusion, in mammals, the endocytic adaptor protein Eps15 is a regulator of B-cell lymphopoiesis.
Standardized, Systemic Phenotypic Analysis of UmodC93F and UmodA227T Mutant Mice
Elisabeth Kemter, Petra Prückl, Birgit Rathkolb, Kateryna Micklich, Thure Adler, Lore Becker, Johannes Beckers, Dirk H. Busch, Alexander A. G?tz, Wolfgang Hans, Marion Horsch, Boris Ivandic, Martin Klingenspor, Thomas Klopstock, Jan Rozman, Anja Schrewe, Holger Schulz, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabé de Angelis, Eckhard Wolf, Bernhard Aigner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078337
Abstract: Uromodulin-associated kidney disease (UAKD) summarizes different clinical features of an autosomal dominant heritable disease syndrome in humans with a proven uromodulin (UMOD) mutation involved. It is often characterized by hyperuricemia, gout, alteration of urine concentrating ability, as well as a variable rate of disease progression inconstantly leading to renal failure and histological alterations of the kidneys. We recently established the two Umod mutant mouse lines UmodC93F and UmodA227T on the C3H inbred genetic background both showing kidney defects analogous to those found in human UAKD patients. In addition, disease symptoms were revealed that were not yet described in other published mouse models of UAKD. To examine if further organ systems and/or metabolic pathways are affected by Umod mutations as primary or secondary effects, we describe a standardized, systemic phenotypic analysis of the two mutant mouse lines UmodA227T and UmodC93F in the German Mouse Clinic. Different genotypes as well as different ages were tested. Beside the already published changes in body weight, body composition and bone metabolism, the influence of the Umod mutation on energy metabolism was confirmed. Hematological analysis revealed a moderate microcytic and erythropenic anemia in older Umod mutant mice. Data of the other analyses in 7-10 month-old mutant mice showed single small additional effects.
Mouse Nuclear Myosin I Knock-Out Shows Interchangeability and Redundancy of Myosin Isoforms in the Cell Nucleus
Tomá? Venit, Rastislav Dzijak, Al?běta Kalendová, Michal Kahle, Jana Roho?ková, Volker Schmidt, Thomas Rülicke, Birgit Rathkolb, Wolfgang Hans, Alexander Bohla, Oliver Eickelberg, Tobias Stoeger, Eckhard Wolf, Ali ?nder Yildirim, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Pavel Hozák
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061406
Abstract: Background Nuclear myosin I (NM1) is a nuclear isoform of the well-known “cytoplasmic” Myosin 1c protein (Myo1c). Located on the 11th chromosome in mice, NM1 results from an alternative start of transcription of the Myo1c gene adding an extra 16 amino acids at the N-terminus. Previous studies revealed its roles in RNA Polymerase I and RNA Polymerase II transcription, chromatin remodeling, and chromosomal movements. Its nuclear localization signal is localized in the middle of the molecule and therefore directs both Myosin 1c isoforms to the nucleus. Methodology/Principal Findings In order to trace specific functions of the NM1 isoform, we generated mice lacking the NM1 start codon without affecting the cytoplasmic Myo1c protein. Mutant mice were analyzed in a comprehensive phenotypic screen in cooperation with the German Mouse Clinic. Strikingly, no obvious phenotype related to previously described functions has been observed. However, we found minor changes in bone mineral density and the number and size of red blood cells in knock-out mice, which are most probably not related to previously described functions of NM1 in the nucleus. In Myo1c/NM1 depleted U2OS cells, the level of Pol I transcription was restored by overexpression of shRNA-resistant mouse Myo1c. Moreover, we found Myo1c interacting with Pol II. The ratio between Myo1c and NM1 proteins were similar in the nucleus and deletion of NM1 did not cause any compensatory overexpression of Myo1c protein. Conclusion/Significance We observed that Myo1c can replace NM1 in its nuclear functions. Amount of both proteins is nearly equal and NM1 knock-out does not cause any compensatory overexpression of Myo1c. We therefore suggest that both isoforms can substitute each other in nuclear processes.
Abnormal Brain Iron Metabolism in Irp2 Deficient Mice Is Associated with Mild Neurological and Behavioral Impairments
Kimberly B. Zumbrennen-Bullough, Lore Becker, Lillian Garrett, Sabine M. H?lter, Julia Calzada-Wack, Ilona Mossbrugger, Leticia Quintanilla-Fend, Ildiko Racz, Birgit Rathkolb, Thomas Klopstock, Wolfgang Wurst, Andreas Zimmer, Eckhard Wolf, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabě de Angelis, Steven J. Romney, Elizabeth A. Leibold
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098072
Abstract: Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role of Irp2 in regulating iron metabolism. While both mouse models show that loss of Irp2 results in microcytic anemia and altered body iron distribution, discrepant results have drawn into question the role of Irp2 in regulating brain iron metabolism. One model shows that aged Irp2 deficient mice develop adult-onset progressive neurodegeneration that is associated with axonal degeneration and loss of Purkinje cells in the central nervous system. These mice show iron deposition in white matter tracts and oligodendrocyte soma throughout the brain. A contrasting model of global Irp2 deficiency shows no overt or pathological signs of neurodegeneration or brain iron accumulation, and display only mild motor coordination and balance deficits when challenged by specific tests. Explanations for conflicting findings in the severity of the clinical phenotype, brain iron accumulation and neuronal degeneration remain unclear. Here, we describe an additional mouse model of global Irp2 deficiency. Our aged Irp2?/? mice show marked iron deposition in white matter and in oligodendrocytes while iron content is significantly reduced in neurons. Ferritin and transferrin receptor 1 (TfR1, Tfrc), expression are increased and decreased, respectively, in the brain from Irp2?/? mice. These mice show impairments in locomotion, exploration, motor coordination/balance and nociception when assessed by neurological and behavioral tests, but lack overt signs of neurodegenerative disease. Ultrastructural studies of specific brain regions show no evidence of neurodegeneration. Our data suggest that Irp2 deficiency dysregulates brain iron metabolism causing cellular dysfunction that ultimately leads to mild neurological, behavioral and nociceptive impairments.
Usability Experiments to Evaluate UML/SysML-Based Model Driven Software Engineering Notations for Logic Control in Manufacturing Automation  [PDF]
Birgit Vogel-Heuser
Journal of Software Engineering and Applications (JSEA) , 2014, DOI: 10.4236/jsea.2014.711084
Abstract: Many industrial companies and researchers are looking for more efficient model driven engineering approaches (MDE) in software engineering of manufacturing automation systems (MS) especially for logic control programming, but are uncertain about the applicability and effort needed to implement those approaches in comparison to classical Programmable Logic Controller (PLC) programming with IEC 61131-3. The paper summarizes results of usability experiments evaluating UML and SysML as software engineering notations for a MDE applied in the domain of manufacturing systems. Modeling MS needs to cover the domain specific characteristics, i.e. hybrid process, real time requirements and communication requirements. In addition the paper presents factors, constraint and practical experience for the development of further usability experiments. The paper gives examples of notational expressiveness and weaknesses of UML and SysML. The appendix delivers detailed master models, representing the correct best suited model, and evaluation schemes of the experiment, which is helpful if setting up own empirical experiments.
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