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匹配条件: “ Martin Hrab_ de Angelis” ,找到相关结果约197618条。
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Voluntary wheel running in mice increases the rate of neurogenesis without affecting anxiety-related behaviour in single tests
Lillian Garrett, D Chichung Lie, Martin Hrabé de Angelis, Wolfgang Wurst, Sabine M H?lter
BMC Neuroscience , 2012, DOI: 10.1186/1471-2202-13-61
Abstract: Running altered measures of locomotion and exploration, but not anxiety-related behaviour in either test. 14?days running significantly increased proliferation, and differentiation and survival were increased after both running durations. 28?day running mice also exhibited an increased rate of maturation. Furthermore, there was a significant positive correlation between the amount of proliferation, but not maturation, and anxiety measures in the open field of the 28?day running mice.Overall, this evidence suggests that without repeated testing, newly born mature neurons may not be involved in the genesis of anxiety per se.
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
Zebrafish 20β-Hydroxysteroid Dehydrogenase Type 2 Is Important for Glucocorticoid Catabolism in Stress Response
Janina Tokarz, William Norton, Gabriele M?ller, Martin Hrabé de Angelis, Jerzy Adamski
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054851
Abstract: Stress, the physiological reaction to a stressor, is initiated in teleost fish by hormone cascades along the hypothalamus-pituitary-interrenal (HPI) axis. Cortisol is the major stress hormone and contributes to the appropriate stress response by regulating gene expression after binding to the glucocorticoid receptor. Cortisol is inactivated when 11β-hydroxysteroid dehydrogenase (HSD) type 2 catalyzes its oxidation to cortisone. In zebrafish, Danio rerio, cortisone can be further reduced to 20β-hydroxycortisone. This reaction is catalyzed by 20β-HSD type 2, recently discovered by us. Here, we substantiate the hypothesis that 20β-HSD type 2 is involved in cortisol catabolism and stress response. We found that hsd11b2 and hsd20b2 transcripts were up-regulated upon cortisol treatment. Moreover, a cortisol-independent, short-term physical stressor led to the up-regulation of hsd11b2 and hsd20b2 along with several HPI axis genes. The morpholino-induced knock down of hsd20b2 in zebrafish embryos revealed no developmental phenotype under normal culture conditions, but prominent effects were observed after a cortisol challenge. Reporter gene experiments demonstrated that 20β-hydroxycortisone was not a physiological ligand for the zebrafish glucocorticoid or mineralocorticoid receptor but was excreted into the fish holding water. Our experiments show that 20β-HSD type 2, together with 11β-HSD type 2, represents a short pathway in zebrafish to rapidly inactivate and excrete cortisol. Therefore, 20β-HSD type 2 is an important enzyme in stress response.
From Dynamic Expression Patterns to Boundary Formation in the Presomitic Mesoderm
Hendrik B. Tiedemann,Elida Schneltzer,Stefan Zeiser,Bastian Hoesel,Johannes Beckers,Gerhard K. H. Przemeck,Martin Hrabě de Angelis
PLOS Computational Biology , 2012, DOI: 10.1371/journal.pcbi.1002586
Abstract: The segmentation of the vertebrate body is laid down during early embryogenesis. The formation of signaling gradients, the periodic expression of genes of the Notch-, Fgf- and Wnt-pathways and their interplay in the unsegmented presomitic mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into epithelialized structures, the somites. Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we present an enhanced gene regulatory network (GRN) for mice in a simulation program that models the growing PSM by many virtual cells and integrates WNT3A and FGF8 gradient formation, periodic gene expression and Delta/Notch signaling. Assuming Hes7 as core of the somitogenesis clock and LFNG as modulator, we postulate a negative feedback of HES7 on Dll1 leading to an oscillating Dll1 expression as seen in vivo. Furthermore, we are able to simulate the experimentally observed wave of activated NOTCH (NICD) as a result of the interactions in the GRN. We esteem our model as robust for a wide range of parameter values with the Hes7 mRNA and protein decays exerting a strong influence on the core oscillator. Moreover, our model predicts interference between Hes1 and HES7 oscillators when their intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core oscillator that is able to reproduce many experimentally observed data in mice.
MausDB: An open source application for phenotype data and mouse colony management in large-scale mouse phenotyping projects
Holger Maier, Christoph Lengger, Bruno Simic, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabé de Angelis
BMC Bioinformatics , 2008, DOI: 10.1186/1471-2105-9-169
Abstract: We present MausDB, the German Mouse Clinic web-based database application that integrates standard mouse colony management, phenotyping workflow scheduling features and mouse phenotyping result data management. It links mouse phenotype data with genotype data, metadata and external data such as public web databases, which is a prerequisite for comprehensive data analysis and mining. We describe how this can be achieved with a lean and user-friendly system built on open standards.MausDB is suited for large-scale, high-throughput phenotyping facilities but can also be used exclusively for mouse colony management within smaller units or projects. The system is successfully used as the primary mouse and data management tool of the German Mouse Clinic and other mouse facilities. We offer MausDB to the scientific community as open source software to provide a system for storage of data from functional genomics projects in a well-structured, easily accessible form.The concept of standardized, high-throughput and comprehensive screening of mice has proven to be successful for identifying new phenotypes in mutant mouse lines by the German Mouse Clinic (GMC) [1-7] and others [8,9].In the GMC, experts from various fields of mouse behavior, physiology, morphology, metabolism and pathology work side-by-side in one building in 14 individual modules (allergy, behavior, cardiovascular system, clinical chemistry, dysmorphology, energy metabolism, eye development and vision, immunology, lung function, molecular phenotyping, neurology, nociception, pathology and steroid metabolism) in close collaboration with clinicians and veterinarians [2].Mouse mutants and their littermate controls pass through the different modules of the GMC in multi-parallel phenotyping pipelines following a standardized workflow. In the course of the high-throughput primary screen, up to 320 parameters per mouse line are measured, and these findings may be supplemented by results from secondary and tertiary scr
Fast Synchronization of Ultradian Oscillators Controlled by Delta-Notch Signaling with Cis-Inhibition
Hendrik B. Tiedemann,Elida Schneltzer,Stefan Zeiser,Wolfgang Wurst,Johannes Beckers,Gerhard K. H. Przemeck,Martin Hrabě de Angelis
PLOS Computational Biology , 2014, DOI: doi/10.1371/journal.pcbi.1003843
Abstract: While it is known that a large fraction of vertebrate genes are under the control of a gene regulatory network (GRN) forming a clock with circadian periodicity, shorter period oscillatory genes like the Hairy-enhancer-of split (Hes) genes are discussed mostly in connection with the embryonic process of somitogenesis. They form the core of the somitogenesis-clock, which orchestrates the periodic separation of somites from the presomitic mesoderm (PSM). The formation of sharp boundaries between the blocks of many cells works only when the oscillators in the cells forming the boundary are synchronized. It has been shown experimentally that Delta-Notch (D/N) signaling is responsible for this synchronization. This process has to happen rather fast as a cell experiences at most five oscillations from its ‘birth’ to its incorporation into a somite. Computer simulations describing synchronized oscillators with classical modes of D/N-interaction have difficulties to achieve synchronization in an appropriate time. One approach to solving this problem of modeling fast synchronization in the PSM was the consideration of cell movements. Here we show that fast synchronization of Hes-type oscillators can be achieved without cell movements by including D/N cis-inhibition, wherein the mutual interaction of DELTA and NOTCH in the same cell leads to a titration of ligand against receptor so that only one sort of molecule prevails. Consequently, the symmetry between sender and receiver is partially broken and one cell becomes preferentially sender or receiver at a given moment, which leads to faster entrainment of oscillators. Although not yet confirmed by experiment, the proposed mechanism of enhanced synchronization of mesenchymal cells in the PSM would be a new distinct developmental mechanism employing D/N cis-inhibition. Consequently, the way in which Delta-Notch signaling was modeled so far should be carefully reconsidered.
Comparison of particle-exposure triggered pulmonary and systemic inflammation in mice fed with three different diets
Alexander A G?tz, Jan Rozman, Heiko G R?del, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabě de Angelis, Martin Klingenspor, Tobias Stoeger
Particle and Fibre Toxicology , 2011, DOI: 10.1186/1743-8977-8-30
Abstract: In this study we addressed the question, whether a diet challenge increases the inflammatory response in the alveolar and the blood compartment in response to carbon nanoparticles (CNP), as a surrogate for ambient/urban particulate air pollutants.Mice were fed a high caloric carbohydrate-rich (CA) or a fat-rich (HF) diet for six weeks and were compared to mice kept on a purified low fat (LF) diet, respectively. Bronchoalveolar lavage (BAL) and blood samples were taken 24 h after intratracheal CNP instillation and checked for cellular and molecular markers of inflammation.The high caloric diets resulted in distinct effects when compared with LF mice, respectively: CA resulted in increased body and fat mass without affecting blood cellular immunity. Conversely, HF activated the blood system, increasing lymphocyte and neutrophil counts, and resulted in slightly increased body fat content. In contrast to higher pro-inflammatory BAL Leptin in CA and HF mice, on a cellular level, both diets did not lead to an increased pro-inflammatory basal status in the alveolar compartment per se, nor did result in differences in the particle-triggered response. However both diets resulted in a disturbance of the alveolar capillary barrier as indicated by enhanced BAL protein and lactate-dehydrogenase concentrations. Systemically, reduced serum Adiponectin in HF mice might be related to the observed white blood cell increase.The increase in BAL pro-inflammatory factors in high caloric groups and reductions in serum concentrations of anti-inflammatory factors in HF mice, clearly show diet-specific effects, pointing towards augmented systemic inflammatory conditions. Our data suggest that extended feeding periods, leading to manifest obesity, are necessary to generate an increased susceptibility to particle-induced lung inflammation; although the diet-challenge already was efficient in driving pro-inflammatory systemic events.Obesity and its common sequelae (e.g. type II diabetes and car
Expression of Tas1 Taste Receptors in Mammalian Spermatozoa: Functional Role of Tas1r1 in Regulating Basal Ca2+ and cAMP Concentrations in Spermatozoa
Dorke Meyer, Anja Voigt, Patricia Widmayer, Heike Borth, Sandra Huebner, Andreas Breit, Susan Marschall, Martin Hrabé de Angelis, Ulrich Boehm, Wolfgang Meyerhof, Thomas Gudermann, Ingrid Boekhoff
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032354
Abstract: Background During their transit through the female genital tract, sperm have to recognize and discriminate numerous chemical compounds. However, our current knowledge of the molecular identity of appropriate chemosensory receptor proteins in sperm is still rudimentary. Considering that members of the Tas1r family of taste receptors are able to discriminate between a broad diversity of hydrophilic chemosensory substances, the expression of taste receptors in mammalian spermatozoa was examined. Methodology/Principal Findings The present manuscript documents that Tas1r1 and Tas1r3, which form the functional receptor for monosodium glutamate (umami) in taste buds on the tongue, are expressed in murine and human spermatozoa, where their localization is restricted to distinct segments of the flagellum and the acrosomal cap of the sperm head. Employing a Tas1r1-deficient mCherry reporter mouse strain, we found that Tas1r1 gene deletion resulted in spermatogenic abnormalities. In addition, a significant increase in spontaneous acrosomal reaction was observed in Tas1r1 null mutant sperm whereas acrosomal secretion triggered by isolated zona pellucida or the Ca2+ ionophore A23187 was not different from wild-type spermatozoa. Remarkably, cytosolic Ca2+ levels in freshly isolated Tas1r1-deficient sperm were significantly higher compared to wild-type cells. Moreover, a significantly higher basal cAMP concentration was detected in freshly isolated Tas1r1-deficient epididymal spermatozoa, whereas upon inhibition of phosphodiesterase or sperm capacitation, the amount of cAMP was not different between both genotypes. Conclusions/Significance Since Ca2+ and cAMP control fundamental processes during the sequential process of fertilization, we propose that the identified taste receptors and coupled signaling cascades keep sperm in a chronically quiescent state until they arrive in the vicinity of the egg - either by constitutive receptor activity and/or by tonic receptor activation by gradients of diverse chemical compounds in different compartments of the female reproductive tract.
The Pathologic Effect of a Novel Neomorphic Fgf9Y162C Allele Is Restricted to Decreased Vision and Retarded Lens Growth
Oliver Puk, Gabriele M?ller, Arie Geerlof, Kathrin Krowiorz, Nafees Ahmad, Sibylle Wagner, Jerzy Adamski, Martin Hrabé de Angelis, Jochen Graw
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023678
Abstract: Fibroblast growth factor (Fgf) signalling plays a crucial role in many developmental processes. Among the Fgf pathway ligands, Fgf9 (UniProt: P54130) has been demonstrated to participate in maturation of various organs and tissues including skeleton, testes, lung, heart, and eye. Here we establish a novel Fgf9 allele, discovered in a dominant N-ethyl-N-nitrosourea (ENU) screen for eye-size abnormalities using the optical low coherence interferometry technique. The underlying mouse mutant line Aca12 was originally identified because of its significantly reduced lens thickness. Linkage studies located Aca12 to chromosome 14 within a 3.6 Mb spanning interval containing the positional candidate genes Fgf9 (MGI: 104723), Gja3 (MGI: 95714), and Ift88 (MGI: 98715). While no sequence differences were found in Gja3 and Ift88, we identified an A→G missense mutation at cDNA position 770 of the Fgf9 gene leading to an Y162C amino acid exchange. In contrast to previously described Fgf9 mutants, Fgf9Y162C carriers were fully viable and did not reveal reduced body-size, male-to-female sexual reversal or skeletal malformations. The histological analysis of the retina as well as its basic functional characterization by electroretinography (ERG) did not show any abnormality. However, the analysis of head-tracking response of the Fgf9Y162C mutants in a virtual drum indicated a gene-dosage dependent vision loss of almost 50%. The smaller lenses in Fgf9Y162C suggested a role of Fgf9 during lens development. Histological investigations showed that lens growth retardation starts during embryogenesis and continues after birth. Young Fgf9Y162C lenses remained transparent but developed age-related cataracts. Taken together, Fgf9Y162C is a novel neomorphic allele that initiates microphakia and reduced vision without effects on organs and tissues outside the eye. Our data point to a role of Fgf9 signalling in primary and secondary lens fiber cell growth. The results underline the importance of allelic series to fully understand multiple functions of a gene.
In Vivo Functional Requirement of the Mouse Ifitm1 Gene for Germ Cell Development, Interferon Mediated Immune Response and Somitogenesis
Ingeborg Klymiuk, Lukas Kenner, Thure Adler, Dirk H. Busch, Auke Boersma, Martin Irmler, Valérie Gailus-Durner, Helmut Fuchs, Nicole Leitner, Mathias Müller, Ralf Kühn, Michaela Schlederer, Irina Treise, Martin Hrabě de Angelis, Johannes Beckers
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044609
Abstract: The mammalian Interferon induced transmembrane protein 1 (Ifitm1) gene was originally identified as a member of a gene family highly inducible by type I and type II interferons. Based on expression analyses, it was suggested to be required for normal primordial germ cell migration. The knockdown of Ifitm1 in mouse embryos provided evidence for a role in somitogenesis. We generated the first targeted knockin allele of the Ifitm1 gene to systematically reassess all inferred functions. Sperm motility and the fertility of male and female mutant mice are as in wild type littermates. Embryonic somites and the adult vertebral column appear normal in homozygous Ifitm1 knockout mice, demonstrating that Ifitm1 is not essential for normal segmentation of the paraxial mesoderm. Proportions of leucocyte subsets, including granulocytes, monocytes, B-cells, T-cells, NK-cells, and NKT-cells, are unchanged in mutant mice. Based on a normal immune response to Listeria monocytogenes infection, there is no evidence for a dysfunction in downstream IFNγ signaling in Ifitm1 mutant mice. Expression from the Ifitm1 locus from E8.5 to E14.5 is highly dynamic. In contrast, in adult mice, Ifitm1 expression is highly restricted and strong in the bronchial epithelium. Intriguingly, IFITM1 is highly overexpressed in tumor epithelia cells of human squamous cell carcinomas and in adenocarcinomas of NSCLC patients. These analyses underline the general importance of targeted in vivo studies for the functional annotation of the mammalian genome. The first comprehensive description of the Ifitm1 expression pattern provides a rational basis for the further examination of Ifitm1 gene functions. Based on our data, the fact that IFITM1 can function as a negative regulator of cell proliferation, and because the gene maps to chromosome band 11p15.5, previously associated with NSCLC, it is likely that IFITM1 in man has a key role in tumor formation.
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