Anja Schrewe

Publications of Anja Schrewe

• Cardiopulmonary dysfunction in the Osteogenesis Imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms.

  Authors: Frank Thiele, Christian M Cohrs, Armando Flor, Thomas S Lisse, Gerhard K H Przemeck, Marion Horsch, Anja Schrewe, Valerie Gailus-Durner, Boris Ivandic, Hugo A Katus, Wolfgang Wurst, Catherine Reisenberg, Hollis Chaney, Helmut Fuchs, Wolfgang Hans, Johannes Beckers, Joan C Marini, Martin Hrabé de Angelis

  Human molecular genetics. 05/2012;

  Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with skeletal dysplasia of varying severity, predominantly caused by mutations in the collagen I genes (COL1A1/COL1A2).Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with skeletal dysplasia of varying severity, predominantly caused by mutations in the collagen I genes (COL1A1/COL1A2). Extraskeletal findings like cardiac and pulmonary complications are generally considered to be significant secondary features. Aga2, a murine model for human OI, was systemically analyzed in the German Mouse Clinic by means of in vivo and in vitro examinations of the cardiopulmonary system, to identify novel mechanisms accounting for perinatal lethality. Pulmonary and especially cardiac fibroblast of perinatal lethal Aga2/+ animals display a strong down-regulation of Col1a1 transcripts in vivo and in vitro, resulting in loss of extracellular matrix integrity. In addition, dysregulated gene expression of Nppa, different types of collagen and Agt in heart and lung tissue supports a bone-independent vicious cycle of heart dysfunction including hypertrophy, loss of myocardial matrix integrity, pulmonary hypertension, pneumonia and hypoxia leading to death in Aga2. These murine findings are corroborated by a pediatric OI cohort study, displaying significant progressive decline of pulmonary function and restrictive pulmonary disease independent of scoliosis. Most participants show mild cardiac valvular regurgitation, independent of pulmonary and skeletal findings. Data obtained from human OI patients and the mouse model Aga2 provide novel evidence for primary effects of type I collagen mutations on heart and lung. The findings will have potential benefits of anticipatory clinical exams and early intervention in OI patients.

• Requirement of the RNA-editing enzyme ADAR2 for normal physiology in mice.

  Authors: Marion Horsch, Peter H Seeburg, Thure Adler, Juan Antonio Aguilar-Pimentel, Lore Becker, Julia Calzada-Wack, Lilian Garrett, Alexander Götz, Wolfgang Hans, Miyoko Higuchi [......] Martin Mempel, Markus Ollert, Holger Schulz, Eckhard Wolf, Wolfgang Wurst, Andreas Zimmer, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Johannes Beckers

  The Journal of biological chemistry. 04/2011; 286(21):18614-22.

  ADAR2, an RNA editing enzyme that converts specific adenosines to inosines in certain pre-mRNAs, often leading to amino acid substitutions in the encoded proteins, is mainly expressed in brain. OfADAR2, an RNA editing enzyme that converts specific adenosines to inosines in certain pre-mRNAs, often leading to amino acid substitutions in the encoded proteins, is mainly expressed in brain. Of all ADAR2-mediated edits, a single one in the pre-mRNA of the AMPA receptor subunit GluA2 is essential for survival. Hence, early postnatal death of mice lacking ADAR2 is averted when the critical edit is engineered into both GluA2 encoding Gria2 alleles. Adar2(-/-)/Gria2(R/R) mice display normal appearance and life span, but the general phenotypic effects of global lack of ADAR2 have remained unexplored. Here we have employed the Adar2(-/-)/Gria2(R/R) mouse line, and Gria2(R/R) mice as controls, to study the phenotypic consequences of loss of all ADAR2-mediated edits except the critical one in GluA2. Our extended phenotypic analysis covering ∼320 parameters identified significant changes related to absence of ADAR2 in behavior, hearing ability, allergy parameters and transcript profiles of brain.

• Mouse phenotyping.

  Authors: Helmut Fuchs, Valérie Gailus-Durner, Thure Adler, Juan Antonio Aguilar-Pimentel, Lore Becker, Julia Calzada-Wack, Patricia Da Silva-Buttkus, Frauke Neff, Alexander Götz, Wolfgang Hans [......] Elisabeth Kremmer, Martin Mempel, Susanne Neschen, Markus Ollert, Holger Schulz, Karsten Suhre, Eckhard Wolf, Wolfgang Wurst, Andreas Zimmer, Martin Hrabě de Angelis

  Methods (San Diego, Calif.). 02/2011; 53(2):120-35.

  Model organisms like the mouse are important tools to learn more about gene function in man. Within the last 20 years many mutant mouse lines have been generated by different methods such as ENUModel organisms like the mouse are important tools to learn more about gene function in man. Within the last 20 years many mutant mouse lines have been generated by different methods such as ENU mutagenesis, constitutive and conditional knock-out approaches, knock-down, introduction of human genes, and knock-in techniques, thus creating models which mimic human conditions. Due to pleiotropic effects, one gene may have different functions in different organ systems or time points during development. Therefore mutant mouse lines have to be phenotyped comprehensively in a highly standardized manner to enable the detection of phenotypes which might otherwise remain hidden. The German Mouse Clinic (GMC) has been established at the Helmholtz Zentrum München as a phenotyping platform with open access to the scientific community (www.mousclinic.de; [1]). The GMC is a member of the EUMODIC consortium which created the European standard workflow EMPReSSslim for the systemic phenotyping of mouse models (http://www.eumodic.org/[2]).

• Mutation of the Na(+)-K(+)-2Cl(-) cotransporter NKCC2 in mice is associated with severe polyuria and a urea-selective concentrating defect without hyperreninemia.

  Authors: Elisabeth Kemter, Birgit Rathkolb, Lise Bankir, Anja Schrewe, Wolfgang Hans, Christina Landbrecht, Matthias Klaften, Boris Ivandic, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabé de Angelis, Eckhard Wolf, Ruediger Wanke, Bernhard Aigner

  American journal of physiology. Renal physiology. 03/2010; 298(6):F1405-15.

  The bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter NKCC2, located in the thick ascending limb of Henle's loop, plays a critical role in the kidney's ability to concentrate urine. In humans,The bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter NKCC2, located in the thick ascending limb of Henle's loop, plays a critical role in the kidney's ability to concentrate urine. In humans, loss-of-function mutations of the solute carrier family 12 member 1 gene (SLC12A1), coding for NKCC2, cause type I Bartter syndrome, which is characterized by prenatal onset of a severe polyuria, salt-wasting tubulopathy, and hyperreninemia. In this study, we describe a novel chemically induced, recessive mutant mouse line termed Slc12a1(I299F) exhibiting late-onset manifestation of type I Bartter syndrome. Homozygous mutant mice are viable and exhibit severe polyuria, metabolic alkalosis, marked increase in plasma urea but close to normal creatininemia, hypermagnesemia, hyperprostaglandinuria, hypotension,, and osteopenia. Fractional excretion of urea is markedly decreased. In addition, calcium and magnesium excretions are more than doubled compared with wild-type mice, while uric acid excretion is twofold lower. In contrast to hyperreninemia present in human disease, plasma renin concentration in homozygotes is not increased. The polyuria observed in homozygotes may be due to the combination of two additive factors, a decrease in activity of mutant NKCC2 and an increase in medullary blood flow, due to prostaglandin-induced vasodilation, that impairs countercurrent exchange of urea in the medulla. In conclusion, this novel viable mouse line with a missense Slc12a1 mutation exhibits most of the features of type I Bartter syndrome and may represent a new model for the study of this human disease.

• Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration.

  Authors: Christoph Kleinschnitz, Henrike Grund, Kirstin Wingler, Melanie E Armitage, Emma Jones, Manish Mittal, David Barit, Tobias Schwarz, Christian Geis, Peter Kraft [......] Anja Schrewe, Lore Becker, Valérie Gailus-Durner, Helmut Fuchs, Thomas Klopstock, Martin Hrabé de Angelis, Karin Jandeleit-Dahm, Ajay M Shah, Norbert Weissmann, Harald H H W Schmidt

  PLoS biology. 01/2010; 8(9).

  Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical needIschemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.

• Novel Missense Mutation of Uromodulin in Mice Causes Renal Dysfunction with Alterations in Urea Handling, Energy and Bone Metabolism.

  Authors: Elisabeth Kemter, Birgit Rathkolb, Jan Rozman, Wolfgang Hans, Anja Schrewe, Christina Landbrecht, Matthias Klaften, Boris T Ivandic, Helmut Fuchs, Valerie Gailus-Durner, Martin Klingenspor, Martin Hrabe de Angelis, Eckhard Wolf, Ruediger Wanke, Bernhard Aigner

  American journal of physiology. Renal physiology. 09/2009;

  Uromodulin-associated kidney disease is a heritable renal disease in humans caused by mutations in the uromodulin (UMOD) gene. The pathogenesis of the disease is mostly unknown. In this study, weUromodulin-associated kidney disease is a heritable renal disease in humans caused by mutations in the uromodulin (UMOD) gene. The pathogenesis of the disease is mostly unknown. In this study, we describe a novel chemically induced mutant mouse line termed Umod(A227T) exhibiting impaired renal function. The A227T amino acid exchange may impair uromodulin trafficking, leading to dysfunction of thick ascending limb cells of Henle's loop of the kidney. As a consequence, homozygous mutant mice display azotemia, impaired urine concentration ability, reduced fractional excretion of uric acid and a selective defect to concentrate urea. Osteopenia in mutant mice is presumably a result of chronic hypercalciuria. In addition, body composition, lipid and energy metabolism are indirectly affected in heterozygous and homozygous mutant Umod(A227T) mice, manifesting in reduced body weight, fat mass and metabolic rate as well as reduced blood cholesterol, triglycerides, and non-esterified fatty acids. In conclusion, Umod(A227T) might act as gain-of-toxic-function mutation. Therefore, the Umod(A227T) mouse line provides novel insights into consequences of disturbed uromodulin excretion regarding renal dysfunction as well as bone, energy and lipid metabolism. Key words: N-ethyl-N-nitrosourea, kidney, renal disease, Umod.

• A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice.

  Authors: Wolfgang Enard, Sabine Gehre, Kurt Hammerschmidt, Sabine M Hölter, Torsten Blass, Mehmet Somel, Martina K Brückner, Christiane Schreiweis, Christine Winter, Reinhard Sohr [......] Eckhard Wolf, Wolfgang Wurst, Andreas Zimmer, Simon E Fisher, Rudolf Morgenstern, Thomas Arendt, Martin Hrabé de Angelis, Julia Fischer, Johannes Schwarz, Svante Pääbo

  Cell. 06/2009; 137(5):961-71.

  It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here,It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting that the humanized Foxp2 allele affects basal ganglia. In the striatum, a part of the basal ganglia affected in humans with a speech deficit due to a nonfunctional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one nonfunctional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans.

• Dll1 haploinsufficiency in adult mice leads to a complex phenotype affecting metabolic and immunological processes.

  Authors: Isabel Rubio-Aliaga, Gerhard K H Przemeck, Helmut Fuchs, Valérie Gailus-Durner, Thure Adler, Wolfgang Hans, Marion Horsch, Birgit Rathkolb, Jan Rozman, Anja Schrewe [......] 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. 02/2009; 4(6):e6054.

  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.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 (Dll1(C413Y)). 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.

• Systemic First-Line Phenotyping.

  Authors: Valérie Gailus-Durner, Helmut Fuchs, Thure Adler, Antonio Aguilar-Pimentel, Lore Becker, Ines Bolle, Julia Calzada-Wack, Claudia Dalke, Nicole Ehrhardt, Barbara Ferwagner [......] Boris Ivandic, Hugo Katus, Martin Klingenspor, Thomas Elisabeth Kremmer, Markus Ollert, Leticia Quintanilla-Martinez, Holger Schulz, Eckhard Wolf, Wolfgang Wurst, Martin de Angelis

  Methods in molecular biology (Clifton, N.J.). 02/2009; 530:1-47.

  With the completion of the mouse genome sequence an essential task for biomedical sciences in the twenty-first century will be the generation and functional analysis of mouse models for every gene inWith the completion of the mouse genome sequence an essential task for biomedical sciences in the twenty-first century will be the generation and functional analysis of mouse models for every gene in the mammalian genome. More than 30,000 mutations in ES cells will be engineered and thousands of mouse disease models will become available over the coming years by the collaborative effort of the International Mouse Knockout Consortium. In order to realize the full value of the mouse models proper characterization, archiving and dissemination of mouse disease models to the research community have to be performed. Phenotyping centers (mouse clinics) provide the necessary capacity, broad expertise, equipment, and infrastructure to carry out large-scale systemic first-line phenotyping. Using the example of the German Mouse Clinic (GMC) we will introduce the reader to the different aspects of the organization of a mouse clinic and present selected methods used in first-line phenotyping.

• Pleiotropic effects in Eya3 knockout mice.

  Authors: Torben Soker, Claudia Dalke, Oliver Puk, Thomas Floss, Lore Becker, Ines Bolle, Jack Favor, Wolfgang Hans, Sabine Hoelter, Marion Horsch [......] Johannes Beckers, Helmut Fuchs, Boris Ivandic, Thomas Klopstock, Holger Schulz, Eckhard Wolf, Wolfgang Wurst, Laure Bally-Cuif, Martin Hrabe de Angelis, Jochen Graw

  BMC developmental biology. 01/2009; 8(1):118.

  ABSTRACT: BACKGROUND: In Drosophila, mutations in the gene eyes absent (eya) lead to severe defects in eye development. The functions of its mammalian orthologs Eya1-4 are only partially understoodABSTRACT: BACKGROUND: In Drosophila, mutations in the gene eyes absent (eya) lead to severe defects in eye development. The functions of its mammalian orthologs Eya1-4 are only partially understood and no mouse model exists for Eya3. Therefore, we characterized the phenotype of a new Eya3 knockout mouse mutant. RESULTS: Expression analysis of Eya3 by in-situ hybridizations and beta-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. CONCLUSION: 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.

• "Sighted C3H" mice--a tool for analysing the influence of vision on mouse behaviour?

  Authors: Sabine M Hoelter, Claudia Dalke, Magdalena Kallnik, Lore Becker, Marion Horsch, Anja Schrewe, Jack Favor, Thomas Klopstock, Johannes Beckers, Boris Ivandic, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabé de Angelis, Jochen Graw, Wolfgang Wurst

  Frontiers in bioscience : a journal and virtual library. 02/2008; 13:5810-23.

  It is unclear what role vision plays in guiding mouse behaviour, since the mouse eye is of comparably low optical quality, and mice are considered to rely primarily on other senses. All C3HIt is unclear what role vision plays in guiding mouse behaviour, since the mouse eye is of comparably low optical quality, and mice are considered to rely primarily on other senses. All C3H substrains are homozygous for the Pde6b(rd1) mutation and get blind by weaning age. To study the impact of the Pde6b(rd1) mutation on mouse behaviour and physiology, sighted C3H (C3H.Pde6b+) and normal C3H/HeH mice were phenotyped for different aspects. We confirmed retinal degeneration 1 in C3H/HeH mice, and the presence of a morphologically normal retina as well as visual ability in C3H.Pde6b+ mice. However, C3H.Pde6b+ mice showed an abnormal retinal function in the electroretinogram response, indicating that their vision was not normal as expected. C3H.Pde6b+ mice showed reduced latencies for several behaviours without any further alterations in these behaviours in comparison to C3H/HeH mice, suggesting that visual ability, although impaired, enables earlier usage of the behavioural repertoire in a novel environment, but does not lead to increased activity levels. These results emphasize the importance of comprehensive behavioural and physiological phenotyping.

• Pleiotropic effects in Eya3 knockout mice

  Authors: Torben Söker, Claudia Dalke, Oliver Puk, Thomas Floss, Lore Becker, Ines Bolle, Jack Favor, Wolfgang Hans, Sabine Hölter, Marion Horsch [......] Johannes Beckers, Helmut Fuchs, Boris Ivandic, Thomas Klopstock, Holger Schulz, Eckhard Wolf, Wolfgang Wurst, Laure Bally-Cuif, de Angelis Martin, Jochen Graw

  BMC Developmental Biology. 01/2008;

  Abstract Background In Drosophila , mutations in the gene eyes absent ( eya ) lead to severe defects in eye development. The functions of its mammalian orthologs Eya1-4 are only partiallyAbstract Background In Drosophila , mutations in the gene eyes absent ( eya ) lead to severe defects in eye development. The functions of its mammalian orthologs Eya1-4 are only partially understood and no mouse model exists for Eya3 . Therefore, we characterized the phenotype of a new Eya3 knockout mouse mutant. Results 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. Conclusion 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.

• Atrial natriuretic peptide and osteopontin are useful markers of cardiac disorders in mice.

  Authors: Frank Schoensiegel, Raffi Bekeredjian, Anja Schrewe, Dieter Weichenhan, Norbert Frey, Hugo A Katus, Boris T Ivandic

  Comparative medicine. 01/2008; 57(6):546-53.

  Biomarkers are not established for cardiovascular phenotyping in mice. We compared the use of echocardiography with the determination of N-terminal propeptide of the atrial natriuretic peptideBiomarkers are not established for cardiovascular phenotyping in mice. We compared the use of echocardiography with the determination of N-terminal propeptide of the atrial natriuretic peptide (Nt-proANP) and osteopontin (Opn). We measured plasma Nt-proANP and Opn levels in (1) the inbred strains C57BL/6, BALB/c, C3H/He, DBA/2, FVB/N, 129S1/Sv; (2) a surgical model of nonischemic myocardial infarction; and (3) delta-sarcoglycan (Sgcd) and calsarcin 1 [also known as myozenin 2 (Myoz2)] knockout models of cardiomyopathy. Left ventricular function was assessed as fractional shortening (FS) by echocardiography in conscious mice. Plasma Nt-proANP exhibited marked variability and ranged from 0.31 +/- 0.19 (C57BL/6 male mice) to 1.34 +/- 0.43 nmol/l (DBA/2 female mice), depending on sex, age, and genetic background. Opn was less variable than Nt-proANP and was decreased significantly in C3H/He and DBA/2 throughout the 16 wk of study. Nt-proANP increased temporarily in mice with myocardial injury. In contrast, Opn increased in both operated and sham-treated mice. Nt-proANP was inversely correlated with FS and distinguished controls from Sgcd and Myoz2 mutants with 100% sensitivity and 71% specificity. Opn was increased in Sgcd mutants, which exhibited only mildly reduced FS but marked myocardial degeneration and fibrosis. Both of these histologic features were absent in Myoz2 mutants. Nt-proANP is an early marker of cardiac disease and is suitable for age- and sex-matched comparisons between groups of transgenic and matched control mice. Opn is useful to detect inflammatory and degenerative myocardial disorders that may be missed by echocardiography.

• Introducing the German Mouse Clinic: open access platform for standardized phenotyping.

  Authors: Valérie Gailus-Durner, Helmut Fuchs, Lore Becker, Ines Bolle, Markus Brielmeier, Julia Calzada-Wack, Ralf Elvert, Nicole Ehrhardt, Claudia Dalke, Tobias J Franz [......] Frauke Ohl, Markus Ollert, Leticia Quintanilla-Martinez, Jörg Schmidt, Holger Schulz, Eckhard Wolf, Wolfgang Wurst, Andreas Zimmer, Dirk H Busch, Martin Hrabé de Angelis

  Nature methods. 07/2005; 2(6):403-4.

• Mouse phenotyping

  Authors: Helmut Fuchs, Valérie Gailus-Durner, Thure Adler, Juan Antonio Aguilar-Pimentel, Lore Becker, Julia Calzada-Wack, Patricia Da Silva-Buttkus, Frauke Neff, Alexander Götz, Wolfgang Hans [......] Elisabeth Kremmer, Martin Mempel, Susanne Neschen, Markus Ollert, Holger Schulz, Karsten Suhre, Eckhard Wolf, Wolfgang Wurst, Andreas Zimmer, Martin Hrabě de Angelis

  Methods.

  Model organisms like the mouse are important tools to learn more about gene function in man. Within the last 20 years many mutant mouse lines have been generated by different methods such as ENUModel organisms like the mouse are important tools to learn more about gene function in man. Within the last 20 years many mutant mouse lines have been generated by different methods such as ENU mutagenesis, constitutive and conditional knock-out approaches, knock-down, introduction of human genes, and knock-in techniques, thus creating models which mimic human conditions. Due to pleiotropic effects, one gene may have different functions in different organ systems or time points during development. Therefore mutant mouse lines have to be phenotyped comprehensively in a highly standardized manner to enable the detection of phenotypes which might otherwise remain hidden. The German Mouse Clinic (GMC) has been established at the Helmholtz Zentrum München as a phenotyping platform with open access to the scientific community (www.mousclinic.de; [1]). The GMC is a member of the EUMODIC consortium which created the European standard workflow EMPReSSslim for the systemic phenotyping of mouse models (http://www.eumodic.org/[2]).