Latest news from German Mouse Clinic Latest news from German Mouse Clinic en Latest news from German Mouse Clinic 18 16 Latest news from German Mouse Clinic TYPO3 - get.content.right Fri, 28 Apr 2017 09:39:00 +0200 SRF and its role in acute stress response The brain is the central organ that ensures immediate and long-term adaptions to stress. Acute... c-Fos and Egr family members. IEG transcription in neurons is mediated by the neuronal activity-driven gene regulator serum response factor (SRF). We demonstrate a role of SRF in immediate and long-lasting acute restraint stress responses. The scientists around Annemarie Zimprich and Gabi Mroz analyzed the serum response factor (SRF), a neuronal activity-induced transcription factor. As previously shown by analysis of Srf mouse mutants, SRF triggers a neuronal IEG response elicited by various stimuli including epileptic seizures, growth factors, or exposure to a novel environment. Impaired IEG induction in Srf mutant mice was associated with failed habituation to a novel object, hyperactivity, impaired conditioned reinforcement, and resilience to CS. In this study, adult mice with an SRF deletion in glutamatergic neurons (Srf; CaMKIIa-CreERT2) were analysed at the German Mouse Clinic including behavioral, metabolic, cardiologic testing and gene expression profiling. The mice showed hyperactivity, decreased anxiety, and impaired working memory. In response to restraint AS, instant stress reactivity consisting of locomotor activation and corticosterone induction was impaired in Srf mutant mice. Hyperactivity was even preserved over 6 months suggesting long-term molecular and cellular changes inflicted by SRF ablation on neuronal networks. These findings support previous reports on SRF ablation confined to hippocampal or dopaminoceptive neurons all describing hyperactivity and impaired memory formation. In summary, the findings suggest a role of SRF in immediate AS reactions and long-term stress coping mechanisms.

Annemarie Zimprich & Gabi Mroz & Christopher Meyer zu Reckendorf & Sofia Anastasiadou & Philip Förstner & Lillian Garrett & Sabine M. Hölter & Lore Becker & Jan Rozman & Cornelia Prehn & Birgit Rathkolb & Kristin Moreth & Wolfgang Wurst & Thomas Klopstock & Martin Klingenspor & Jerzy Adamski & Eckhard Wolf & Raffi Bekeredjian & Helmut Fuchs & Valerie Gailus-Durner & Martin Hrabe de Angelis & Bernd Knöll. Serum Response Factor (SRF) Ablation Interferes with Acute Stress-Associated Immediate and Long-Term Coping Mechanisms. Mol Neurobiol. 2016 Dec 2. [Epub ahead of print]. Doi: 10.1007/s12035-016-0300-x

Fri, 28 Apr 2017 09:39:00 +0200
Spermidine – cardioprotection and life span extension Cardiovascular disease has reached epidemic proportions in the aging society and remains the... Tobias Eisenberg, Mahmoud Abdellatif, Sabrina Schroeder, Uwe Primessnig, Slaven Stekovic, Tobias Pendl, Alexandra Harger, Julia Schipke, Andreas Zimmermann, Albrecht Schmidt, Mingming Tong, Christoph Ruckenstuhl, Christopher Dammbrueck, Angelina S Gross, Viktoria Herbst, Christoph Magnes, Gert Trausinger, Sophie Narath, Andreas Meinitzer, Zehan Hu, Alexander Kirsch, Kathrin Eller, Didac Carmona-Gutierrez, Sabrina Büttner, Federico Pietrocola, Oskar Knittelfelder, Emilie Schrepfer, Patrick Rockenfeller, Corinna Simonini, Alexandros Rahn, Marion Horsch, Kristin Moreth, Johannes Beckers, Helmut Fuchs, Valerie Gailus-Durner, Frauke Neff, Dirk Janik, Birgit Rathkolb, Jan Rozman, Martin Hrabe de Angelis, Tarek Moustafa, Guenter Haemmerle, Manuel Mayr, Peter Willeit, Marion von Frieling-Salewsky, Burkert Pieske, Luca Scorrano, Thomas Pieber, Raimund Pechlaner, Johann Willeit, Stephan J Sigrist, Wolfgang A Linke, Christian Mühlfeld, Junichi Sadoshima, Joern Dengjel, Stefan Kiechl, Guido Kroemer, Simon Sedej & Frank Madeo. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016 Dec;22(12):1428-1438. doi: 10.1038/nm.4222.]]> Fri, 21 Apr 2017 09:47:00 +0200 AOX integration as a tool to study mitochondrial pathology In many lower organism and plants, alternative oxidases (AOXs) are expressed that bypass the... To study disruptions and impairments in the mitochondrial respiratory chain, AOX from Ciona intestinalis, a marine tunicate with very soft tunic, has been integrated into mammalian cell lines, Drosophila disease models and, recently, in the mouse. These experiments showed that the deleterious consequences of toxic or pathological inhibition of the downstream portion of the mitochondrial respiratory chain, specifically OXPHOS complexes III (cIII) and IV (cIV), which AOX bypasses, were averted. The scientists around Marten Szibor proposed that the expression of AOX in commonly studied animal models could be used to elucidate the pathophysiology underlying mitochondrial OXPHOS disorders, providing a rational basis for its eventual implementation in therapeutic applications.
Therefore they created a genetically tractable transgenic mouse that ubiquitously expresses a single copy of Ciona AOX at substantial levels, after targeted insertion into the Rosa26 locus, a locus used for constitutive, ubiquitous gene expression in mice. The Rosa26 knock-in gave rise to a functional enzyme, which conferred resistance to respiratory poisons. Surprisingly, comprehensive phenotyping in the GMC revealed only minor, biologically inconsequential effects of AOX expression in the AOXRosa26 mouse. The authors expect that new model will be a promising tool for elucidating the mechanisms of mitochondrial pathology and charting the way towards future therapies. Marten Szibor, Praveen K. Dhandapani, Eric Dufour, Kira M. Holmström, Yuan Zhuang, Isabelle Salwig, Ilka Wittig, Juliana Heidler, Zemfira Gizatullina, Timur Gainutdinov, German Mouse Clinic Consortium, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabě de Angelis, Jatin Nandania, Vidya Velagapudi, Astrid Wietelmann, Pierre Rustin, Frank N. Gellerich, Howard T. Jacobs, and Thomas Braun. Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology. Dis Model Mech. 2017 Feb 1;10(2):163-171. doi: 10.1242/dmm.027839.]]>
Fri, 31 Mar 2017 10:14:00 +0200
Scube 3 – a mouse model for Paget disease of bone? The vertebrate Scube (Signal peptide, CUB and EGF-like domain-containing protein) family consists... Scube (Signal peptide, CUB and EGF-like domain-containing protein) family consists of three independent members Scube1-3, which encode secreted cell surface-associated membrane glycoproteins. Little is known about the general function of this gene family, and the roles of the family members during adulthood. However, one major function appears to be in bone development and homeostasis and another one in neurological functions. The new mutant mouse line presented by Fuchs and colleagues carries a missense mutation in exon 8 of the Scube3 gene (Scube3N294K/N294K). To better understand the Scube3 gene function the mutant mouse line was phenotypically characterized in the German Mouse Clinic (GMC). Scube3N294K/N294K mutants showed morphological abnormalities of the skeleton, alterations of parameters relevant for bone metabolism, changes in renal function and hearing impairments. These findings correlate with characteristics of the rare metabolic bone disorder Paget disease of bone (PDB), associated with the chromosomal region of human SCUBE3. PDB1 is characterized by focal areas of increased bone turnover. Human SCUBE3 was originally identified following transcriptional profiling of vascular endothelial cells and demonstrated significant enrichment in primary osteoblasts and long bones.
In addition, in Scube3N294K/N294K mice alterations in energy metabolism, behavior and neurological functions were detected. The Scube3N294K/N294K mutant mouse line may serve as a new model for further studying the effect of impaired SCUBE3 gene function. Fuchs H, Sabrautzki S, Przemeck GK, Leuchtenberger S, Lorenz-Depiereux B, Becker L, Rathkolb B, Horsch M, Garrett L, Östereicher MA, Hans W, Abe K, Sagawa N, Rozman J, Vargas-Panesso IL, Sandholzer M, Lisse TS, Adler T, Aguilar-Pimentel JA, Calzada-Wack J, Ehrhard N, Elvert R, Gau C, Hölter SM, Micklich K, Moreth K, Prehn C, Puk O, Racz I, Stoeger C, Vernaleken A, Michel D, Diener S, Wieland T, Adamski J, Bekeredjian R, Busch DH, Favor J, Graw J, Klingenspor M, Lengger C, Maier H, Neff F, Ollert M, Stoeger T, Yildirim AÖ, Strom TM, Zimmer A, Wolf E, Wurst W, Klopstock T, Bekers J, Gailus-Durner V, Hrabé de Angelis M. The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations. G3 (Bethesda). 2016 Dec 7;6(12):4035-4046. doi: 10.1534/g3.116.033670.]]>
Fri, 03 Feb 2017 15:04:00 +0100
Conjugated glucagon & thyroid hormones – novel therapeutic option for metabolic syndrome? Dyslipidemia, including hypercholesterolemia and hypertriglyceridemia, represents a hallmark of the... Thyroid hormones powerfully influence systemic metabolism through multiple pathways, with profound effects on energy expenditure, fat oxidation, and cholesterol metabolism. However, when used as thyroid hormone treatment, adverse side effects occur, including increased heart rate, cardiac hypertrophy, muscle wasting, and reduced bone density. Until now, discovery of thyromimetics capable of separating lipid metabolism benefits from adverse cardiovascular effects has remained a desire. A pharmacological agent that lowers cholesterol, triglycerides, glucose, hepatic fat, and body weight would offer a transformative advancement for treatment of the metabolic syndrome that should decrease mortality risk from cardiovascular events. Scientists around Brian Finan from the Institute for Diabetes and Obesity at the Helmholtz Diabetes Center at Helmholtz Zentrum München engineered chemical conjugates that deliver the desired activities of glucogen and thyroid Hormone within one molecule while at the same time the inherent harmful effects of each molecule are reduced.
Of the intense studies in mice that were treated with conjugated glucagon and T3 effects on body temperature regulation, the cardiovascular system and cardiopathology were studied in the German Mouse Clinic. Summing up the scientists showed that glucagon-mediated selective delivery of thyroid hormone to the liver results in coordinated actions that synergize to correct hyperlipidemia, reverse hepatic steatosis, and lower body weight through liver- and fat-specific mechanisms. The liver-directed thyroid hormone action overrides the diabetogenic liability of local glucagon action resulting in a net improvement of glycemic control, while glucagon-mediated delivery spares adverse action of thyroid hormone, notably on the cardiovascular system. Finan B, Clemmensen C, Zhu Z, Stemmer K, Gauthier K, Müller L, De Angelis M, Moreth K, Neff F, Perez-Tilve D, Fischer K, Lutter D, Sánchez-Garrido MA, Liu P, Tuckermann J, Malehmir M, Healy ME, Weber A, Heikenwalder M, Jastroch M, Kleinert M, Jall S, Brandt S, Flamant F, Schramm KW, Biebermann H, Döring Y, Weber C, Habegger KM, Keuper M, Gelfanov V, Liu F, Köhrle J, Rozman J, Fuchs H, Gailus-Durner V, Hrabě de Angelis M, Hofmann SM, Yang B, Tschöp MH, DiMarchi R, Müller TD. Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease. Cell. 2016 Oct 20;167(3):843-857.e14. doi: 10.1016/j.cell.2016.09.014. Epub 2016 Oct 6.]]>
Fri, 03 Feb 2017 14:59:00 +0100
Sms1 and its role in male infertility Sphingolipids are essential components of cellular membranes and are required for lipid raft... de novo synthesis of sphingomyelin (SM) and diacylglycerol (DAG) from ceramide (Cer) and phosphatidylcholine (PC). SM and other complex sphingolipids (SL) have various functions in structure, adhesion and signaling. Loss of function mutations of various catabolic enzymes of the sphingolipid pathway can lead to lipid storage diseases such as Niemann-Pick, Gaucher's, Tay-Sachs and others. Scientists around Thomas Floss and Tobias Hartmann analyzed the role of SMS1 in testis. During sperm maturation, the sphingolipid metabolism is an essential process. Several mutations in enzymes of the SL metabolism caused severely impaired fertility. The scientists created an insertional mutation in the gene for the anabolic enzyme SMS1 and studied its consequences for male fertility.

Among several investigations, RNA expression profiling as well as pathology was performed in the German Mouse Clinic. Taken together, the result of the different analyses showed that infertility was observed in 66% of Sms1 homozygous mutant adult males. Infertility was caused by sloughing of meiotic and spermatid stages with subsequent accumulation in the epididymides. In addition, the injection of fluorescent dyes demonstrated a defective Blood-Testis Barrier (BTB). Lipid profiling of testes revealed a decrease of LC-PUFAs in Sms1-/- animals. Male infertility was ameliorated by supplementary diet of DHA and EPA ('fish oil'), indicating an essential role for SMS1 in the supply with n-3 unsaturated long-chain FA substrates for the formation of the BTB and the syncytium. Wittmann A, Grimm MO, Scherthan H, Horsch M, Beckers J, Fuchs H, Gailus-Durner V, Hrabě de Angelis M, Ford SJ, Burton NC, Razansky D, Trümbach D, Aichler M, Walch AK, Calzada-Wack J, Neff F, Wurst W, Hartmann T, Floss T. Sphingomyelin Synthase 1 Is Essential for Male Fertility in Mice. PLoS One. 2016 Oct 27;11(10):e0164298. doi: 10.1371/journal.pone.0164298. eCollection 2016.]]>
Fri, 03 Feb 2017 08:40:00 +0100
Ednra – mouse model for human mandibulofacial dysostosis with alopecia (MFDA) syndrome Endothelin 1 (EDN1,2)–endothelin receptor type A (EDNRA) signaling seems to play an important role... The scientists around Sibylle Sabrautzki from the Institute of Experimental Genetics at the Helmholtz Zentrum München performed standardized phenotyping of wild-type, heterozygous, and homozygous EdnraY129F mice within the German Mouse Clinic.
Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process. Mutant EdnraY129F mice also exhibit hearing impairment in line with strong abnormalities of the ossicles and further, reduction of some lung volumetric parameters. In general, heterozygous and homozygous mice demonstrated inter-individual diversity of expression of the craniofacial phenotypes. Many of these phenotypes were also observed or described for MFDA patients. Thus the mutant EdnraY129F mice seem to be a valuable viable model for complex human syndromes of the first and second pharyngeal arches, the understanding of the human MFDA syndrome and for the development of therapeutic interventions. Sibylle Sabrautzki, Michael A. Sandholzer, Bettina Lorenz-Depiereux, Robert Brommage, Gerhard Przemeck, Ingrid L. Vargas Panesso, Alexandra Vernaleken, Lillian Garrett, Katharina Baron, Ali O. Yildirim, Jan Rozman, Birgit Rathkolb, Christine Gau, Wolfgang Hans, Sabine M. Hoelter, Susan Marschall, Claudia Stoeger, Lore Becker, Helmut Fuchs, Valerie Gailus-Durner, Martin Klingenspor, Thomas Klopstock, Christoph Lengger, Leuchtenberger Stefanie, Eckhard Wolf, Tim M. Strom, Wolfgang Wurst, Martin Hrabeˇ de Angelis. Viable EdnraY129F mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation. Mamm Genome (2016) 27:587–598. DOI 10.1007/s00335-016-9664-5]]>
Fri, 16 Dec 2016 13:00:00 +0100
Soluble biglycan induces EPO production and polycythemia Polycythemia is a disease characterized by an increased number of mature erythrocytes in the... Epo, a protein of 30 kDa, is in adults mainly produced in the kidney by interstitial cells and to some degree in the liver by hepatocytes. Epo is a crucial regulator of erythropoiesis that stimulates the proliferation and terminal differentiation of erythroid precursor cells. Therefore, administration of recombinant Epo has become the standard treatment for anemia in chronic kidney disease.

There is growing evidence that components of the extracellular matrix (ECM) have not only a structural function within the ECM but may also act in their soluble form as signaling molecules. Biglycan, a class I small leucine-rich proteoglycan, is proteolytically released from the ECM upon tissue stress or injury as a soluble molecule thereby acting as a danger signal. As an endogenous ligand of the innate immune receptors such as Toll-like receptor (TLR)-2 and -4, soluble biglycan promotes inflammation via its ability to evoke the expression of proinflammatory cytokines and chemokines.

Prof. Liliana Schaefer and scientists from the Institut für allgemeine Pharmakologie und Toxikologie at the Klinikum of the Goethe-Universität Frankfurt generated a transgenic mouse model, in which biglycan was constitutively overexpressed and secreted by hepatocytes (BGNTg). As a consequence biglycan was constantly released into the blood stream. BGNTg mice were systematically phenotyped in the German Mouse Clinic. The mice harbored an increase in mature circulating erythrocytes, elevated hemoglobin concentrations, hematocrit values and enhanced total iron binding capacity – clinical signs of polycythemia. Further experiments showed that i) BGNTg mutants had enhanced Epo mRNA expression in the liver and kidney, while elevated Epo protein levels were found in liver, kidney and blood.  ii) the transgenic animals had an abundance of HIF-2α protein in the liver and kidney. The transient overexpression of circulating biglycan in mice deficient in various Toll-like receptors (TLRs) revealed a novel function of biglycan. It promotes Epo synthesis by a selective interaction with TLR2. This process works presumably in an oxygen-independent manner, ultimately giving rise to secondary polycythemia. Frey H & Moreth K, Hsieh LT, Zeng-Brouwers J, Rathkolb B, Fuchs H, Gailus-Durner V, Iozzo RV, de Angelis MH, Schaefer L. A novel biological function of soluble biglycan: Induction of erythropoietin production and polycythemia. Glycoconj J. 2016 Sep 6. 2016]]>
Fri, 25 Nov 2016 09:42:00 +0100
CIP2As function in the immune system The oncoprotein Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) has been documented to be a...
Christophe Côme, Anna Cvrljevic, Mohd Moin Khan, Irina Treise, Thure Adler, Juan Antonio Aguilar-Pimentel, Byron Au-Yeung, Eleonora Sittig, Teemu Daniel Laajala, Yiling Chen, Sebastian Oeder, Julia Calzada-Wack, Marion Horsch, Tero Aittokallio, Dirk H. Busch, Markus W. Ollert, Frauke Neff, Johannes Beckers, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Zhi Chen, Riitta Lahesmaa, Jukka Westermarck. CIP2A Promotes T-Cell Activation and Immune Response to Listeria monocytogenes Infection. 2016. PLoS ONE 11(4): e0152996. Doi: ]]>
Fri, 30 Sep 2016 09:38:00 +0200
Pts and its role in obesity Tetrahydrobiopterin (BH4) is an essential cofactor for the aromatic amino acid hydroxylases,...
Germaine Korner, Tanja Scherer, Dea Adamsen, Alexander Rebuffat, Mark Crabtree, Anahita Rassi, Rossana Scavelli, Daigo Homma, Birgit Ledermann, Daniel Konrad, Hiroshi Ichinose, Christian Wolfrum, Marion Horsch, Birgit Rathkolb, Martin Klingenspor, Johannes Beckers, Eckhard Wolf, Valérie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Nenad Blau, Jan Rozman, Beat Thöny: Mildly compromised tetrahydrobiopterin cofactor biosynthesis due to Pts variants leads to unusual body fat distribution and abdominal obesity in mice. J Inherit Metab Dis (2016) 39:309–319. DOI 10.1007/s10545-015-9909-6]]>
Fri, 16 Sep 2016 08:41:00 +0200