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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 Hlter
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.
MAPK Signaling Determines Anxiety in the Juvenile Mouse Brain but Depression-Like Behavior in Adults
Benedikt Wefers, Christiane Hitz, Sabine M. Hlter, Dietrich Trümbach, Jens Hansen, Peter Weber, Benno Pütz, Jan M. Deussing, Martin Hrabé de Angelis, Till Roenneberg, Fang Zheng, Christian Alzheimer, Alcino Silva, Wolfgang Wurst, Ralf Kühn
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035035
Abstract: MAP kinase signaling has been implicated in brain development, long-term memory, and the response to antidepressants. Inducible Braf knockout mice, which exhibit protein depletion in principle forebrain neurons, enabled us to unravel a new role of neuronal MAPK signaling for emotional behavior. Braf mice that were induced during adulthood showed normal anxiety but increased depression-like behavior, in accordance with pharmacological findings. In contrast, the inducible or constitutive inactivation of Braf in the juvenile brain leads to normal depression-like behavior but decreased anxiety in adults. In juvenile, constitutive mutants we found no alteration of GABAergic neurotransmission but reduced neuronal arborization in the dentate gyrus. Analysis of gene expression in the hippocampus revealed nine downregulated MAPK target genes that represent candidates to cause the mutant phenotype. Our results reveal the differential function of MAPK signaling in juvenile and adult life phases and emphasize the early postnatal period as critical for the determination of anxiety in adults. Moreover, these results validate inducible gene inactivation as a new valuable approach, allowing it to discriminate between gene function in the adult and the developing postnatal brain.
FGF/FGFR2 Signaling Regulates the Generation and Correct Positioning of Bergmann Glia Cells in the Developing Mouse Cerebellum
Florian Meier, Florian Giesert, Sabit Delic, Theresa Faus-Kessler, Friederike Matheus, Antonio Simeone, Sabine M. Hlter, Ralf Kühn, Daniela M. Vogt. Weisenhorn, Wolfgang Wurst, Nilima Prakash
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101124
Abstract: The normal cellular organization and layering of the vertebrate cerebellum is established during embryonic and early postnatal development by the interplay of a complex array of genetic and signaling pathways. Disruption of these processes and of the proper layering of the cerebellum usually leads to ataxic behaviors. Here, we analyzed the relative contribution of Fibroblast growth factor receptor 2 (FGFR2)-mediated signaling to cerebellar development in conditional Fgfr2 single mutant mice. We show that during embryonic mouse development, Fgfr2 expression is higher in the anterior cerebellar primordium and excluded from the proliferative ventricular neuroepithelium. Consistent with this finding, conditional Fgfr2 single mutant mice display the most prominent defects in the anterior lobules of the adult cerebellum. In this context, FGFR2-mediated signaling is required for the proper generation of Bergmann glia cells and the correct positioning of these cells within the Purkinje cell layer, and for cell survival in the developing cerebellar primordium. Using cerebellar microexplant cultures treated with an FGFR agonist (FGF9) or antagonist (SU5402), we also show that FGF9/FGFR-mediated signaling inhibits the outward migration of radial glia and Bergmann glia precursors and cells, and might thus act as a positioning cue for these cells. Altogether, our findings reveal the specific functions of the FGFR2-mediated signaling pathway in the generation and positioning of Bergmann glia cells during cerebellar development in the mouse.
Pleiotropic effects in Eya3 knockout mice
Torben S?ker, Claudia Dalke, Oliver Puk, Thomas Floss, Lore Becker, Ines Bolle, Jack Favor, Wolfgang Hans, Sabine M Hlter, Marion Horsch, Magdalena Kallnik, Eva Kling, Corinna Moerth, Anja Schrewe, Christian Stigloher, Stefanie Topp, Valerie Gailus-Durner, Beatrix Naton, Johannes Beckers, Helmut Fuchs, Boris Ivandic, Thomas Klopstock, Holger Schulz, Eckhard Wolf, Wolfgang Wurst, Laure Bally-Cuif, Martin de Angelis, Jochen Graw
BMC Developmental Biology , 2008, DOI: 10.1186/1471-213x-8-118
Abstract: Expression analysis of Eya3 by in-situ hybridizations and β-Gal-staining of Eya3 mutant mice revealed abundant expression of the gene throughout development, e.g. in brain, eyes, heart, somites and limbs suggesting pleiotropic effects of the mutated gene. A similar complex expression pattern was observed also in zebrafish embryos.The phenotype of young adult Eya3 mouse mutants was systematically analyzed within the German Mouse Clinic. There was no obvious defect in the eyes, ears and kidneys of Eya3 mutant mice. Homozygous mutants displayed decreased bone mineral content and shorter body length. In the lung, the tidal volume at rest was decreased, and electrocardiography showed increased JT- and PQ intervals as well as decreased QRS amplitude. Behavioral analysis of the mutants demonstrated a mild increase in exploratory behavior, but decreased locomotor activity and reduced muscle strength. Analysis of differential gene expression revealed 110 regulated genes in heart and brain. Using real-time PCR, we confirmed Nup155 being down regulated in both organs.The loss of Eya3 in the mouse has no apparent effect on eye development. The wide-spread expression of Eya3 in mouse and zebrafish embryos is in contrast to the restricted expression pattern in Xenopus embryos. The loss of Eya3 in mice leads to a broad spectrum of minor physiological changes. Among them, the mutant mice move less than the wild-type mice and, together with the effects on respiratory, muscle and heart function, the mutation might lead to more severe effects when the mice become older. Therefore, future investigations of Eya3 function should focus on aging mice.Eya3 is one of four mammalian orthologous genes (Eya1-4) of eyes absent (eya) in Drosophila melanogaster [1,2]. Previous investigations demonstrated that a homozygous knockout of eya function in D. melanogaster results in severe embryonic defects and absence of compound eyes due to eye progenitor cell death [3,4]. Like eyes absent in Drosophil
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. Hlter, 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.
Neurobeachin, a Regulator of Synaptic Protein Targeting, Is Associated with Body Fat Mass and Feeding Behavior in Mice and Body-Mass Index in Humans
Pawel K. Olszewski,Jan Rozman,Josefin A. Jacobsson,Birgit Rathkolb,Siv Str?mberg,Wolfgang Hans,Anica Klockars,Johan Alsi?,Ulf Risérus,Lore Becker,Sabine M. Hlter,Ralf Elvert,Nicole Ehrhardt,Valérie Gailus-Durner,Helmut Fuchs,Robert Fredriksson,Eckhard Wolf,Thomas Klopstock,Wolfgang Wurst,Allen S. Levine,Claude Marcus,Martin Hrabě de Angelis,Martin Klingenspor,Helgi B. Schi?th ?,Manfred W. Kilimann ?
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002568
Abstract: Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development and functioning of central and neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient for Nbea have higher body weight due to increased adipose tissue mass. In several feeding paradigms, heterozygous KO mice consumed more food than wild-type (WT) controls, and this consumption was primarily driven by calories rather than palatability. Expression analysis of feeding-related genes in the hypothalamus and brainstem with real-time PCR showed differential expression of a subset of neuropeptide or neuropeptide receptor mRNAs between WT and Nbea+/? mice in the sated state and in response to food deprivation, but not to feeding reward. In humans, we identified two intronic NBEA single-nucleotide polymorphisms (SNPs) that are significantly associated with body-mass index (BMI) in adult and juvenile cohorts. Overall, data obtained in mice and humans suggest that variation of Nbea abundance or activity critically affects body weight, presumably by influencing the activity of feeding-related neural circuits. Our study emphasizes the importance of neural mechanisms in body weight control and points out NBEA as a potential risk gene in human obesity.
A Broad Phenotypic Screen Identifies Novel Phenotypes Driven by a Single Mutant Allele in Huntington’s Disease CAG Knock-In Mice
Sabine M. Hlter, Mary Stromberg, Marina Kovalenko, Lillian Garrett, Lisa Glasl, Edith Lopez, Jolene Guide, Alexander G?tz, Wolfgang Hans, Lore Becker, Birgit Rathkolb, Jan Rozman, Anja Schrewed, Martin Klingenspor, Thomas Klopstock, Holger Schulz, Eckhard Wolf, Wolfgang Wursta, Tammy Gillis, Hiroko Wakimoto, Jonathan Seidman, Marcy E. MacDonald, Susan Cotman, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Jong-Min Lee, Vanessa C. Wheeler
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080923
Abstract: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.
Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System
John F. Staropoli, Larissa Haliw, Sunita Biswas, Lillian Garrett, Sabine M. Hlter, Lore Becker, Sergej Skosyrski, Patricia Da Silva-Buttkus, Julia Calzada-Wack, Frauke Neff, Birgit Rathkolb, Jan Rozman, Anja Schrewe, Thure Adler, Oliver Puk, Minxuan Sun, Jack Favor, Ildikó Racz, Raffi Bekeredjian, Dirk H. Busch, Jochen Graw, Martin Klingenspor, Thomas Klopstock, Eckhard Wolf, Wolfgang Wurst, Andreas Zimmer, Edith Lopez, Hayat Harati, Eric Hill, Daniela S. Krause, Jolene Guide, Ella Dragileva, Evan Gale, Vanessa C. Wheeler, Rose-Mary Boustany, Diane E. Brown, Sylvie Breton, Klaus Ruether, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Susan L. Cotman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038310
Abstract: Cln3Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3Δex7/8 mice. Homozygous Cln3Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10–14 weeks of age. Homozygous Cln3Δex7/8 mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12–13 week old homozygous Cln3Δex7/8mice, which were also seen to a lesser extent in heterozygous Cln3Δex7/8 mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15–16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3Δex7/8 mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3Δex7/8 neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3Δex7/8 mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3Δex7/8 mice that merit further study for JNCL biomarker development.
kompakt 50 - ventilator with heat regenerate
Heinz Hlter
Acta Montanistica Slovaca , 2000,
Abstract: In the paper presents ventilator with heat regenerate. The apparaturs are manufactured by f. H lter, GmbH, and it patent schould. The quality aur in interier is on line relation to different alergical disease (Sick Building Syndrom - SBS).Ventilator with heat regenerate have result in improved of interiors air quality in whick a man dwelled more as 90 % of life.
Evaluating the Quality of Colorectal Cancer Care across the Interface of Healthcare Sectors
Sabine Ludt, Elisabeth Urban, J?rg Eckardt, Stefanie Wache, Bj?rn Broge, Petra Kaufmann-Kolle, Günther Heller, Antje Miksch, Katharina Glassen, Katja Hermann, Regine B?lter, Dominik Ose, Stephen M. Campbell, Michel Wensing, Joachim Szecsenyi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060947
Abstract: Background Colorectal cancer (CRC) has a high prevalence in western countries. Diagnosis and treatment of CRC is complex and requires multidisciplinary collaboration across the interface of health care sectors. In Germany, a new nationwide established program aims to provide quality information of healthcare delivery across different sectors. Within this context, this study describes the development of a set of quality indicators charting the whole pathway of CRC-care including data specifications that are necessary to operationalize these indicators before practice testing. Methods Indicators were developed following a systematic 10 step modified ‘RAND/UCLA Appropriateness Method’ which involved a multidisciplinary panel of thirteen participants. For each indicator in the final set, data specifications relating to sources of quality information, data collection procedures, analysis and feedback were described. Results The final indicator set included 52 indicators covering diagnostic procedures (11 indicators), therapeutic management (28 indicators) and follow-up (6 indicators). In addition, 7 indicators represented patient perspectives. Primary surgical tumor resection and pre-operative radiation (rectum carcinoma only) were perceived as most useful tracer procedures initiating quality data collection. To assess the quality of CRC care across sectors, various data sources were identified: medical records, administrative inpatient and outpatient data, sickness-funds billing code systems and patient survey. Conclusion In Germany, a set of 52 quality indicators, covering necessary aspects across the interfaces and pathways relevant to CRC-care has been developed. Combining different sectors and sources of health care in quality assessment is an innovative and challenging approach but reflects better the reality of the patient pathway and experience of CRC-care.
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