Valérie Gailus-Durner

Publications of Valérie Gailus-Durner

• Neurobeachin, a regulator of synaptic protein targeting, is associated with body fat mass and feeding behavior in mice and body-mass index in humans.

  Authors: Pawel K Olszewski, Jan Rozman, Josefin A Jacobsson, Birgit Rathkolb, Siv Strömberg, Wolfgang Hans, Anica Klockars, Johan Alsiö, Ulf Risérus, Lore Becker [......] Robert Fredriksson, Eckhard Wolf, Thomas Klopstock, Wolfgang Wurst, Allen S Levine, Claude Marcus, Martin Hrabě de Angelis, Martin Klingenspor, Helgi B Schiöth, Manfred W Kilimann

  PLoS genetics. 03/2012; 8(3):e1002568.

  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, NbeaNeurobeachin (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.

• 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.

• Missing-in-metastasis MIM/MTSS1 promotes actin assembly at intercellular junctions and is required for integrity of kidney epithelia.

  Authors: Juha Saarikangas, Pieta K Mattila, Markku Varjosalo, Miia Bovellan, Janne Hakanen, Julia Calzada-Wack, Monica Tost, Luise Jennen, Birgit Rathkolb, Wolfgang Hans [......] Eckhard Wolf, Martin Hrabé de Angelis, Mikko J Frilander, Harri Savilahti, Hannu Sariola, Kirsi Sainio, Sanna Lehtonen, Jussi Taipale, Marjo Salminen, Pekka Lappalainen

  Journal of cell science. 03/2011; 124(Pt 8):1245-55.

  MIM/MTSS1 is a tissue-specific regulator of plasma membrane dynamics, whose altered expression levels have been linked to cancer metastasis. MIM deforms phosphoinositide-rich membranes through itsMIM/MTSS1 is a tissue-specific regulator of plasma membrane dynamics, whose altered expression levels have been linked to cancer metastasis. MIM deforms phosphoinositide-rich membranes through its I-BAR domain and interacts with actin monomers through its WH2 domain. Recent work proposed that MIM also potentiates Sonic hedgehog (Shh)-induced gene expression. Here, we generated MIM mutant mice and found that full-length MIM protein is dispensable for embryonic development. However, MIM-deficient mice displayed a severe urinary concentration defect caused by compromised integrity of kidney epithelia intercellular junctions, which led to bone abnormalities and end-stage renal failure. In cultured kidney epithelial (MDCK) cells, MIM displayed dynamic localization to adherens junctions, where it promoted Arp2/3-mediated actin filament assembly. This activity was dependent on the ability of MIM to interact with both membranes and actin monomers. Furthermore, results from the mouse model and cell culture experiments suggest that full-length MIM is not crucial for Shh signaling, at least during embryogenesis. Collectively, these data demonstrate that MIM modulates interplay between the actin cytoskeleton and plasma membrane to promote the maintenance of intercellular contacts in kidney epithelia.

• 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]).

• Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells.

  Authors: Monika Raab, Sven Kappel, Andrea Krämer, Mourad Sanhaji, Yves Matthess, Elisabeth Kurunci-Csacsko, Julia Calzada-Wack, Birgit Rathkolb, Jan Rozman, Thure Adler [......] Eckhard Wolf, Nicole Sänger, Florian Prinz, Martin Hrabě de Angelis, Jost Seibler, Juping Yuan, Martin Bergmann, Rainald Knecht, Bertolt Kreft, Klaus Strebhardt

  Nature communications. 01/2011; 2:395.

  High attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drugHigh attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drug development, the role of Plk1 in primary cells remains widely unexplored. Therefore, we evaluated the utility of an RNA interference-based model to assess responses to an inducible knockdown (iKD) of Plk1 in adult mice. Here we show that Plk1 silencing can be achieved in several organs, although adverse events are rare. We compared responses in Plk1-iKD mice with those in primary cells kept under controlled culture conditions. In contrast to the addiction of many cancer cell lines to the non-oncogene Plk1, the primary cells' proliferation, spindle assembly and apoptosis exhibit only a low dependency on Plk1. Responses to Plk1-depletion, both in cultured primary cells and in our iKD-mouse model, correspond well and thus provide the basis for using validated iKD mice in predicting responses to therapeutic interventions.

• Urocortin 3 modulates social discrimination abilities via corticotropin-releasing hormone receptor type 2.

  Authors: Jan M Deussing, Johannes Breu, Claudia Kühne, Magdalena Kallnik, Mirjam Bunck, Lisa Glasl, Yi-Chun Yen, Mathias V Schmidt, Regine Zurmühlen, Annette M Vogl, Valérie Gailus-Durner, Helmut Fuchs, Sabine M Hölter, Carsten T Wotjak, Rainer Landgraf, Martin Hrabé de Angelis, Florian Holsboer, Wolfgang Wurst

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 07/2010; 30(27):9103-16.

  Urocortin 3 (UCN3) is strongly expressed in specific nuclei of the rodent brain, at sites distinct from those expressing urocortin 1 and urocortin 2, the other endogenous ligands ofUrocortin 3 (UCN3) is strongly expressed in specific nuclei of the rodent brain, at sites distinct from those expressing urocortin 1 and urocortin 2, the other endogenous ligands of corticotropin-releasing hormone receptor type 2 (CRH-R2). To determine the physiological role of UCN3, we generated UCN3-deficient mice, in which the UCN3 open reading frame was replaced by a tau-lacZ reporter gene. By means of this reporter gene, the nucleus parabrachialis and the premammillary nucleus were identified as previously unknown sites of UCN3 expression. Additionally, the introduced reporter gene enabled the visualization of axonal projections of UCN3-expressing neurons from the superior paraolivary nucleus to the inferior colliculus and from the posterodorsal part of the medial amygdala to the principal nucleus of the bed nucleus of the stria terminalis, respectively. The examination of tau-lacZ reporter gene activity throughout the brain underscored a predominant expression of UCN3 in nuclei functionally connected to the accessory olfactory system. Male and female mice were comprehensively phenotyped but none of the applied tests provided indications for a role of UCN3 in the context of hypothalamic-pituitary-adrenocortical axis regulation, anxiety- or depression-related behavior. However, inspired by the prevalent expression throughout the accessory olfactory system, we identified alterations in social discrimination abilities of male and female UCN3 knock-out mice that were also present in male CRH-R2 knock-out mice. In conclusion, our results suggest a novel role for UCN3 and CRH-R2 related to the processing of social cues and to the establishment of social memories.

• 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.

• Loss of the actin remodeler Eps8 causes intestinal defects and improved metabolic status in mice.

  Authors: Arianna Tocchetti, Charlotte Blanche Ekalle Soppo, Fabio Zani, Fabrizio Bianchi, Maria Cristina Gagliani, Benedetta Pozzi, Jan Rozman, Ralf Elvert, Nicole Ehrhardt, Birgit Rathkolb [......] Valérie Gailus-Durner, Johannes Beckers, Martin Klingenspor, Eckhard Wolf, Martin Hrabé de Angelis, Eugenio Scanziani, Carlo Tacchetti, Giorgio Scita, Pier Paolo Di Fiore, Nina Offenhäuser

  PloS one. 01/2010; 5(3):e9468.

  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. HereIn a variety of organisms, including mammals, caloric restriction improves metabolic status and lowers the incidence of chronic-degenerative diseases, ultimately leading to increased lifespan. Here we show that knockout mice for Eps8, a regulator of actin dynamics, display reduced body weight, partial resistance to age- or diet-induced obesity, and overall improved metabolic status. Alteration in the liver gene expression profile, in behavior and metabolism point to a calorie restriction-like phenotype in Eps8 knockout mice. Additionally, and consistent with a calorie restricted metabolism, Eps8 knockout mice show increased lifespan. The metabolic alterations in Eps8 knockout mice correlated with a significant reduction in intestinal fat absorption presumably caused by a 25% reduction in intestinal microvilli length. Our findings implicate actin dynamics as a novel variable in the determination of longevity. Additionally, our observations suggest that subtle differences in energy balance can, over time, significantly affect bodyweight and metabolic status in mice.

• Clinical chemistry of mice congenic for QTL for response to Trypanosoma congolense infection.

  Authors: Birgit Rathkolb, Harry A Noyes, Andy Brass, Paul Dark, Helmut Fuchs, Valérie Gailus-Durner, John Gibson, Martin Hrabé de Angelis, Moses Ogugo, Fuad Iraqi, Steve J. Kemp, Jan Naessens, Mathew E. Pope, Eckhard Wolf, Morris Agaba

  Infection and immunity. 08/2009;

  Trypanosoma congolense is a protozoan parasite that causes severe diseases in livestock. Three major quantative trait loci (QTL) (Tir1, Tir2 and Tir3) control the survival time of mice afterTrypanosoma congolense is a protozoan parasite that causes severe diseases in livestock. Three major quantative trait loci (QTL) (Tir1, Tir2 and Tir3) control the survival time of mice after infection with T. congolense. Congenic mice carrying the C57BL/6 resistance alleles on the A/J background were developed for each of these loci. The congenic mice were used to physically map the regions containing the QTL gene(s) and to investigate the physiological effect of each locus. Clinical chemistry data for infected A/J, C57BL/6 and BALB/c mice were obtained for 15 analytes at five time points. Congenic mice were assessed for survival, parasitaemia and anaemia, and 7 clinical-chemical analytes. The survival times were significantly increased in the Tir1 and Tir2 but not Tir3 congenic mice. The survival time of the parental inbred mice correlated negatively with parasitaemia, but positively with alanine aminotransferase (ALAT) activities in serum, suggesting that inflammatory reactions in the liver had a beneficial effect possibly associated with reduced parasitaemia. However, there was no difference in parasitaemia or liver enzyme activities of Tir1 and Tir2 congenic mice relative to their controls, showing that survival, parasitaemia and degree of liver damage are not associated with each other, despite the correlation in the parental lines. These data suggest that the congenic loci affect survival, but do not affect control of parasite number. They may therefore act by limiting the pathological consequences of T. congolense infection.

• 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.

• Expression Pattern of Gpr30 in LacZ Reporter Mice.

  Authors: Jörg Isensee, Luca Meoli, Valeria Zazzu, Christoph Nabzdyk, Henning Witt, Dian Soewarto, Karin Effertz, Helmut Fuchs, Valérie Gailus-Durner, Dirk Busch, Thure Adler, Martin Hrabé de Angelis, Markus Irgang, Christiane Otto, Patricia Ruiz Noppinger

  Endocrinology. 01/2009;

  Multiple reports implicated the function of GPR30 with nongenomic effects of estrogen, suggesting that GPR30 might be a G-protein coupled estrogen receptor. However, the findings are controversialMultiple reports implicated the function of GPR30 with nongenomic effects of estrogen, suggesting that GPR30 might be a G-protein coupled estrogen receptor. However, the findings are controversial and the expression pattern of GPR30 on a cell type level as well as its function in vivo remains unclear. Therefore, the objective of this study was to identify cell types that express Gpr30 in vivo by analyzing a mutant mouse model that harbors a lacZ reporter (Gpr30-lacZ) in the Gpr30 locus leading to a partial deletion of the Gpr30 coding sequence. Using this strategy, we identified the following cell types expressing Gpr30: (I) an endothelial cell subpopulation in small arterial vessels of multiple tissues, (II) smooth muscle cells and pericytes in the brain, (III) gastric chief cells in the stomach, (IV) neuronal subpopulations in the cortex as well as in the polymorph layer of the dentate gyrus, and (V) cell populations in the intermediate and anterior lobe of the pituitary gland as well as (VI) in the medulla of the adrenal gland. In further experiments, we aimed to decipher the function of Gpr30 by analyzing the phenotype of Gpr30-lacZ mice. The body weight as well as fat mass was unchanged in Gpr30-lacZ mice, even if fed with a high fat diet. Flow cytometric analysis revealed lower frequencies of T cells in both sexes of Gpr30-lacZ mice. Within the T cell cluster, the amount of CD62L expressing cells was clearly reduced, suggesting an impaired production of T cells in the thymus of Gpr30-lacZ mice.

• Neurological phenotype and reduced lifespan in heterozygous Tim23 knockout mice, the first mouse model of defective mitochondrial import.

  Authors: Uwe Ahting, Thomas Floss, Nikolas Uez, Ilka Schneider-Lohmar, Lore Becker, Eva Kling, Arcangela Iuso, Andreas Bender, Martin Hrabé de Angelis, Valérie Gailus-Durner, Helmut Fuchs, Thomas Meitinger, Wolfgang Wurst, Holger Prokisch, Thomas Klopstock

  Biochimica et biophysica acta. 01/2009;

  The Tim23 protein is the key component of the mitochondrial import machinery. It locates to the inner mitochondrial membrane and its own import is dependent on the DDP1/TIM13 complex. Mutations inThe Tim23 protein is the key component of the mitochondrial import machinery. It locates to the inner mitochondrial membrane and its own import is dependent on the DDP1/TIM13 complex. Mutations in human DDP1 cause the Mohr-Tranebjaerg syndrome (MTS/DFN-1; OMIM #304700), which is one of the two known human diseases of the mitochondrial protein import machinery. We created a Tim23 knockout mouse from a gene trap embryonic stem cell clone. Homozygous Tim23 mice were not viable. Heterozygous F1 mutants showed a 50% reduction of Tim23 protein in Western blot, a neurological phenotype and a markedly reduced life span. Haploinsufficiency of the Tim23 mutation underlines the critical role of the mitochondrial import machinery for maintaining mitochondrial function.

• "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.

• MausDB: an open source application for phenotype data and mouse colony management in large-scale mouse phenotyping projects.

  Authors: Holger Maier, Christoph Lengger, Bruno Simic, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabé de Angelis

  BMC bioinformatics. 02/2008; 9:169.

  BACKGROUND: Large-scale, comprehensive and standardized high-throughput mouse phenotyping has been established as a tool of functional genome research by the German Mouse Clinic and others. In allBACKGROUND: Large-scale, comprehensive and standardized high-throughput mouse phenotyping has been established as a tool of functional genome research by the German Mouse Clinic and others. In all these projects, vast amounts of data are continuously generated and need to be stored, prepared for data-mining procedures and eventually be made publicly available. Thus, central storage and integrated management of mouse phenotype data, genotype data, metadata and linked external data are highly important. Requirements most probably depend on the individual mouse housing unit or project and the demand for either very specific individual database solutions or very flexible solutions that can be easily adapted to local demands. Not every group has the resources and/or the know-how to develop software for this purpose. A database application has been developed for the German Mouse Clinic in order to meet all requirements mentioned above. RESULTS: 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. CONCLUSION: 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.

• Mouse Phenotype Database Integration Consortium: integration [corrected] of mouse phenome data resources.

  Authors: John M Hancock, Niels C Adams, Vassilis Aidinis, Andrew Blake, Molly Bogue, Steve D M Brown, Elissa J Chesler, Duncan Davidson, Christopher Duran, Janan T Eppig [......] Paul Schofield, Aadya Shukla, Cynthia Smith, Tetsuro Toyoda, Laurent Vasseur, Shigeharu Wakana, Alison Walling, Jacqui White, Joe Wood, Michalis Zouberakis

  Mammalian genome : official journal of the International Mammalian Genome Society. 04/2007; 18(3):157-63.

  Understanding the functions encoded in the mouse genome will be central to an understanding of the genetic basis of human disease. To achieve this it will be essential to be able to characterize theUnderstanding the functions encoded in the mouse genome will be central to an understanding of the genetic basis of human disease. To achieve this it will be essential to be able to characterize the phenotypic consequences of variation and alterations in individual genes. Data on the phenotypes of mouse strains are currently held in a number of different forms (detailed descriptions of mouse lines, first-line phenotyping data on novel mutations, data on the normal features of inbred lines) at many sites worldwide. For the most efficient use of these data sets, we have initiated a process to develop standards for the description of phenotypes (using ontologies) and file formats for the description of phenotyping protocols and phenotype data sets. This process is ongoing and needs to be supported by the wider mouse genetics and phenotyping communities to succeed. We invite interested parties to contact us as we develop this process further.

• Systematic, standardized and comprehensive neurological phenotyping of inbred mice strains in the German Mouse Clinic.

  Authors: Ilka Schneider, Werner S Tirsch, Theresa Faus-Kessler, Lore Becker, Eva Kling, Rose-Leah Austin Busse, Andreas Bender, Berend Feddersen, Johannes Tritschler, Helmut Fuchs, Valérie Gailus-Durner, Karl-Hans Englmeier, Martin Hrabé de Angelis, Thomas Klopstock

  Journal of neuroscience methods. 11/2006; 157(1):82-90.

  Neurological and psychiatric disorders are among the most common and most serious health problems in developed countries. Transgenic mouse models mimicking human neurological diseases have providedNeurological and psychiatric disorders are among the most common and most serious health problems in developed countries. Transgenic mouse models mimicking human neurological diseases have provided new insights into development and function of the nervous system. One of the prominent goals of the German National Genome Research Network is the understanding of the in vivo function of single genes and the pathophysiological and clinical consequences of respective mutations. The German Mouse Clinic (GMC) offers a high-throughput primary screen of genetically modified mouse models as well as an in-depth analysis in secondary and tertiary screens covering various fields of mouse physiology. Here we describe the phenotyping methods of the Neurological Screen in the GMC, exemplified in the four inbred mouse lines C57BL/6J, C3HeB/FeJ, BALB/cByJ, and 129S2/SvPas. For our primary screen, we generated "standard operating procedures" that were validated between different laboratories. The phenotyping of inbred strains already showed significant differences in various parameters, thus being a prerequisite for the examination of mutant mouse lines.

• Generation and characterization of dickkopf3 mutant mice.

  Authors: Ivan del Barco Barrantes, Ana Montero-Pedrazuela, Ana Guadaño-Ferraz, Maria-Jesus Obregon, Raquel Martinez de Mena, Valérie Gailus-Durner, Helmut Fuchs, Tobias J Franz, Svetoslav Kalaydjiev, Martina Klempt [......] Juan Bernal, Dirk H Busch, Wolfgang Wurst, Eckhard Wolf, Holger Schulz, Svetlana Shtrom, Erich Greiner, Martin Hrabé de Angelis, Heiner Westphal, Christof Niehrs

  Molecular and cellular biology. 04/2006; 26(6):2317-26.

  dickkopf (dkk) genes encode a small family of secreted Wnt antagonists, except for dkk3, which is divergent and whose function is poorly understood. Here, we describe the generation anddickkopf (dkk) genes encode a small family of secreted Wnt antagonists, except for dkk3, which is divergent and whose function is poorly understood. Here, we describe the generation and characterization of dkk3 mutant mice. dkk3-deficient mice are viable and fertile. Phenotypic analysis shows no major alterations in organ morphology, physiology, and most clinical chemistry parameters. Since Dkk3 was proposed to function as thyroid hormone binding protein, we have analyzed deiodinase activities, as well as thyroid hormone levels. Mutant mice are euthyroid, and the data do not support a relationship of dkk3 with thyroid hormone metabolism. Altered phenotypes in dkk3 mutant mice were observed in the frequency of NK cells, immunoglobulin M, hemoglobin, and hematocrit levels, as well as lung ventilation. Furthermore, dkk3-deficient mice display hyperactivity.