TY  - JOUR
AB  - Congenital heart defects (CHDs), the most common congenital anomalies, are considered to have a significant genetic component. However, despite considerable efforts to identify pathogenic genes in patients with CHDs, few gene variants have been proven as causal. The complexity of the genetic architecture underlying human CHDs likely contributes to this poor genetic discovery rate. However, several other factors are likely to contribute. For example, the level of patient phenotyping required for clinical care may be insufficient for research studies focused on mechanistic discovery. Although several hundred mouse gene knockouts have been described with CHDs, these are generally not phenotyped and described in the same way as CHDs in patients, and thus are not readily comparable. Moreover, most patients with CHDs carry variants of uncertain significance of crucial cardiac genes, further complicating comparisons between humans and mouse mutants. In spite of major advances in cardiac developmental biology over the past 25 years, these advances have not been well communicated to geneticists and cardiologists. As a consequence, the latest data from developmental biology are not always used in the design and interpretation of studies aimed at discovering the genetic causes of CHDs. In this Special Article, while considering other in vitro and in vivo models, we create a coherent framework for accurately modelling and phenotyping human CHDs in mice, thereby enhancing the translation of genetic and genomic studies into the causes of CHDs in patients.
AU  - Henderson, D.J.*
AU  - Alqahtani, A.*
AU  - Chaudhry, B.*
AU  - Cook, A.M.*
AU  - Eley, L.*
AU  - Houyel, L.*
AU  - Hughes, M.*
AU  - Keavney, B.*
AU  - de la Pompa, J.L.*
AU  - Sled, J.*
AU  - Spielmann, N.
AU  - Teboul, L.*
AU  - Zaffran, S.*
AU  - Mill, P.*
AU  - Liu, K.J.*
C1  - 72479
C2  - 56588
CY  - Bidder Building, Station Rd, Histon, Cambridge Cb24 9lf, England
TI  - Beyond genomic studies of congenital heart defects through systematic modelling and phenotyping.
JO  - Dis. Model. Mech.
VL  - 17
IS  - 11
PB  - Company Biologists Ltd
PY  - 2024
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - The mandible plays an essential part in human life and, thus, defects in this structure can dramatically impair the quality of life in patients. Axolotls, unlike humans, are capable of regenerating their lower jaws; however, the underlying mechanisms and their similarity to those in limb regeneration are unknown. In this work, we used morphological, histological, and transcriptomic approaches to analyze the regeneration of lateral resection defects in the axolotl mandible. We found that this structure can regenerate all missing tissues in 90 days through gap minimization, blastema formation, and finally tissue growth, differentiation, and integration. Moreover, transcriptomic comparisons of regenerating mandibles and limbs showed that they share molecular phases of regeneration, that these similarities peak during blastema stages, and that mandible regeneration occurs at a slower pacing. Altogether, our study demonstrates the existence of a shared regenerative program used in two different regenerating body structures with different embryonic origins in the axolotl, and contributes to our understanding of the minimum requirements for a successful regeneration in vertebrates, bringing us closer to understand similar lesions in human mandibles.
AU  - Kramer, J.*
AU  - Aires, R.*
AU  - Keeley, S.D.*
AU  - Schröder, T.A.*
AU  - Lauer, G.M.*
AU  - Sandoval-Guzmán, T.
C1  - 71555
C2  - 56279
CY  - Bidder Building, Station Rd, Histon, Cambridge Cb24 9lf, England
TI  - Axolotl mandible regeneration occurs through mechanical gap closure and a shared regenerative program with the limb.
JO  - Dis. Model. Mech.
VL  - 17
IS  - 9
PB  - Company Biologists Ltd
PY  - 2024
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Growing evidence shows that the lung is an organ prone to injury by diabetes mellitus. However, the molecular mechanisms of these pulmonary complications have not yet been characterized comprehensively. To systematically study the effects of insulin deficiency and hyperglycaemia on the lung, we combined proteomics and lipidomics with quantitative histomorphological analyses to compare lung tissue samples from a clinically relevant pig model for mutant INS gene induced diabetes of youth (MIDY) with samples from wild-type (WT) littermate controls. Among others, the level of pulmonary surfactant-associated protein A (SFTPA1), a biomarker of lung injury, was moderately elevated. Furthermore, key proteins related to humoral immune response and extracellular matrix (ECM) organization were significantly altered in abundance. Importantly, a lipoxygenase pathway was dysregulated as indicated by a 2.5-fold reduction of polyunsaturated fatty acid lipoxygenase ALOX15 levels, associated with corresponding changes in the levels of lipids influenced by this enzyme. Our multi-omics study points to an involvement of reduced ALOX15 levels and an associated lack of eicosanoid switching as mechanisms contributing to a proinflammatory milieu in the lungs of subjects suffering from diabetes mellitus.
AU  - Shashikadze, B.*
AU  - Flenkenthaler, F.*
AU  - Kemter, E.*
AU  - Franzmeier, S.*
AU  - Stöckl, J.B.*
AU  - Haid, M.
AU  - Riols, F.
AU  - Rothe, M.*
AU  - Pichl, L.*
AU  - Renner, S.*
AU  - Blutke, A.*
AU  - Wolf, E.*
AU  - Fröhlich, T.*
C1  - 70913
C2  - 55977
CY  - Bidder Building, Station Rd, Histon, Cambridge Cb24 9lf, England
TI  - Multi-omics analysis of diabetic pig lungs reveals molecular derangements underlying pulmonary complications of diabetes mellitus.
JO  - Dis. Model. Mech.
VL  - 17
IS  - 7
PB  - Company Biologists Ltd
PY  - 2024
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Mouse models are relevant to study the functionality of genes involved in human diseases, however, translation of phenotypes can be challenging. Herein, we investigated genes related to monogenic forms of cardiovascular disease based on the Genomics England PanelApp and aligned them to the International Mouse Phenotyping Consortium data. We found 153 genes associated to cardiomyopathy, cardiac arrhythmias or congenital heart disease in humans, 151 with a one2one mouse orthologs. For 37.7% (57/151) viability and heart data captured by electrocardiography, transthoracic echocardiography, morphology and pathology from embryos and young adult mice was available. In knockout mice, 75.4% (43/57) of these genes showed non-viable phenotypes, whereas records of prenatal, neonatal or infant death in humans were found for 35.1% (20/57). Multisystem phenotypes are common, with 58.8% (20/34) of heterozygous (homozygous lethal) and 78.6% (11/14) of homozygous (viable) mice showing cardiovascular, metabolic/homeostasis, musculoskeletal, hematopoietic, nervous system and/or growth abnormalities mimicking the clinical manifestations observed in patients. This IMPC data is critical beyond cardiac diagnostics given its multisystemic nature that allows detecting abnormalities across physiological systems, providing a valuable resource to understand pleiotropic effects.
AU  - Cacheiro, P.*
AU  - Spielmann, N.
AU  - Mashhadi, H.H.*
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Smedley, D.*
AU  - Hrabě de Angelis, M.
C1  - 67535
C2  - 54098
TI  - Knockout mice represent an important tool for the multisystemic study of human monogenic heart disease.
JO  - Dis. Model. Mech.
VL  - 16
IS  - 5
PY  - 2023
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Understanding the shared genetic aetiology of psychiatric and medical comorbidity in neurodevelopmental disorders (NDDs) could improve patient diagnosis, stratification and treatment options. Rare TANC2 (Tetratricopeptide Repeat, Ankyrin Repeat and Coiled-Coil Containing 2) disrupting variants were disease-causing in NDD patients. This post-synaptic scaffold protein, essential for dendrite formation in synaptic plasticity, plays an unclarified but critical role in development. We here report a novel homozygous-viable Tanc2 disrupted function model where mutant mice were hyperactive and had impaired sensorimotor gating consistent with NDD patient psychiatric endophenotypes. Yet, a multi-systemic analysis revealed the pleiotropic effects of Tanc2 outside the brain such as growth failure and hepatocellular damage. This was associated with aberrant liver function including altered hepatocellular metabolism. Integrative analysis indicates that these disrupted Tanc2 systemic effects relate to interaction with Hippo developmental signalling pathway proteins and will increase the risk for comorbid somatic disease. This highlights how NDD gene pleiotropy can augment medical comorbidity susceptibility underscoring the benefit of holistic NDD patient diagnosis and treatment for which large-scale preclinical functional genomics can provide complementary pleiotropic gene function information.
AU  - Garrett, L.
AU  - da Silva Buttkus, P.
AU  - Rathkolb, B.
AU  - Gerlini, R.
AU  - Becker, L.
AU  - Sanz-Moreno, A.
AU  - Seisenberger, C.
AU  - Zimprich, A.
AU  - Aguilar-Pimentel, J.A.
AU  - Amarie, O.V.
AU  - Cho, Y.-L.
AU  - Kraiger, M.
AU  - Spielmann, N.
AU  - Calzada-Wack, J.
AU  - Marschall, S.
AU  - Busch, D.*
AU  - Schmidt-Weber, C.B.
AU  - Wolf, E.*
AU  - Wurst, W.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hölter, S.M.
AU  - Hrabě de Angelis, M.
C1  - 64027
C2  - 51683
TI  - Post-synaptic scaffold protein TANC2 in psychiatric and somatic disease risk.
JO  - Dis. Model. Mech.
VL  - 15
IS  - 3
PY  - 2022
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Our understanding of the causes and natural course of restless legs syndrome (RLS) is incomplete. The lack of objective diagnostic biomarkers remains a challenge for clinical research and for the development of valid animal models. As a task force of preclinical and clinical scientists, we have previously defined face validity parameters for rodent models of RLS. In this article, we establish new guidelines for the construct validity of RLS rodent models. To do so, we first determined and agreed on the risk, and triggering factors and pathophysiological mechanisms that influence RLS expressivity. We then selected 20 items considered to have sufficient support in the literature, which we grouped by sex and genetic factors, iron-related mechanisms, electrophysiological mechanisms, dopaminergic mechanisms, exposure to medications active in the central nervous system, and others. These factors and biological mechanisms were then translated into rodent bioequivalents deemed to be most appropriate for a rodent model of RLS. We also identified parameters by which to assess and quantify these bioequivalents. Investigating these factors, both individually and in combination, will help to identify their specific roles in the expression of rodent RLS-like phenotypes, which should provide significant translational implications for the diagnosis and treatment of RLS.
AU  - Salminen, A.V.
AU  - Clemens, S.*
AU  - García-Borreguero, D.*
AU  - Ghorayeb, I.*
AU  - Li, Y.*
AU  - Manconi, M.*
AU  - Ondo, W.*
AU  - Rye, D.*
AU  - Siegel, J.M.*
AU  - Silvani, A.*
AU  - Winkelman, J.W.*
AU  - Allen, R.P.*
AU  - Ferré, S.*
C1  - 65902
C2  - 52970
TI  - Consensus guidelines on the construct validity of rodent models of restless legs syndrome.
JO  - Dis. Model. Mech.
VL  - 15
IS  - 8
PY  - 2022
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Susceptibility to doxorubicin-induced nephropathy (DIN), a toxic model for the induction of proteinurie in mice, is related to the single nucleotide polymorphism (SNP) C6418T of the prkdc gene encoding for the DNA repair enzyme DNA-PKcs. In addition, plasminogen (plg) has been reported to play a role in glomerular damage. Here, we investigated the interdependence of both factors for the development of DIN. Genotyping confirmed the SNP of the prkdc gene in C57BL/6 (prkdcC6418/C6418) and 129S1/SvImJ (prkdcT6418/T6418) mice. Intercross of heterozygous 129SB6F1 mice led to 129SB6F2 hybrids with Mendelian inheritance of the SNP. After doxorubicin injection, only homozygous F2 mice with prkdcT6418/T6418 developed proteinuria. Genetic deficiency of plg (plg-/-) in otherwise susceptible 129S1/SvImJ mice led to resistance to DIN. Immunohistochemistry revealed glomerular binding of plg in plg+/+ mice after doxorubicin injection involving histone H2B as plg receptor. In doxorubicin resistant C57BL/6 mice, plg binding was absent. In conclusion, susceptibility to DIN in 129S1/SvImJ mice is determined by a hierarchical two hit process requiring the C6418T SNP in the prdkc gene and subsequent glomerular binding of plasminogen.
AU  - Bohnert, B.N.
AU  - González-Menéndez, I.*
AU  - Dörffel, T.*
AU  - Schneider, J.C.*
AU  - Xiao, M.*
AU  - Janessa, A.*
AU  - Kalo, M.Z.*
AU  - Fehrenbacher, B.*
AU  - Schaller, M.*
AU  - Casadei, N.*
AU  - Amann, K.*
AU  - Daniel, C.*
AU  - Birkenfeld, A.L.
AU  - Grahammer, F.*
AU  - Izem, L.*
AU  - Plow, E.F.*
AU  - Quintanilla-Martinez, L.*
AU  - Artunc, F.
C1  - 62887
C2  - 51140
TI  - Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice.
JO  - Dis. Model. Mech.
VL  - 14
IS  - 9
PY  - 2021
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Gene trapping is a high-throughput approach that has been used to introduce insertional mutations into the genome of mouse embryonic stem (ES) cells. It is performed with generic gene trap vectors that simultaneously mutate and report the expression of the endogenous gene at the site of insertion and provide a DNA sequence tag for the rapid identification of the disrupted gene. Large-scale international efforts assembled a gene trap library of 566,554 ES cell lines with single gene trap integrations distributed throughout the genome. Here, we re-investigated this unique library and identified mutations in 2202 non-coding RNA (ncRNA) genes, in addition to mutations in 12,078 distinct protein-coding genes. Moreover, we found certain types of gene trap vectors preferentially integrating into genes expressing specific long non-coding RNA (lncRNA) biotypes. Together with all other gene-trapped ES cell lines, lncRNA gene-trapped ES cell lines are readily available for functional in vitro and in vivo studies.
AU  - Hansen, J.
AU  - von Melchner, H.*
AU  - Wurst, W.
C1  - 61402
C2  - 50211
CY  - Bidder Building, Station Rd, Histon, Cambridge Cb24 9lf, England
TI  - Mutant non-coding RNA resource in mouse embryonic stem cells.
JO  - Dis. Model. Mech.
VL  - 14
IS  - 2
PB  - Company Biologists Ltd
PY  - 2021
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Large animal models for Duchenne muscular dystrophy (DMD) are crucial for evaluation of diagnostic procedures and treatment strategies. Pigs cloned from male cells lacking DMD exon 52 (DMDΔ52) resemble molecular, clinical and pathological hallmarks of DMD, but die before sexual maturity and cannot be propagated by breeding. Therefore, we generated female DMD+/- carriers. A single founder animal had 11 litters with 29 DMDY/-, 34 DMD+/- as well as 36 male and 29 female wild-type offspring. Breeding with F1 and F2 DMD+/- carriers resulted in additional 114 DMDY/- piglets. With intensive neonatal management, the majority survived for 3-4 months, providing statistically relevant cohorts for experimental studies. Pathological investigations and proteome studies of skeletal muscles and myocardium confirmed the resemblance of human disease mechanisms. Importantly, DMDY/- pigs reveal progressive myocardial fibrosis and increased expression of connexin-43, associated with significantly reduced left ventricular ejection fraction already at age 3 months. Furthermore, behavioral tests provided evidence for impaired cognitive ability. Our breeding cohort of DMDΔ52 pigs and standardized tissue repositories provide important resources for studying DMD disease mechanisms and for testing novel treatment strategies.
AU  - Stirm, M.*
AU  - Fonteyne, L.M.*
AU  - Shashikadze, B.*
AU  - Lindner, M.*
AU  - Chirivi, M.*
AU  - Lange, A.*
AU  - Kaufhold, C.*
AU  - Mayer, C.*
AU  - Medugorac, I.*
AU  - Kessler, B.*
AU  - Kurome, M.*
AU  - Zakhartchenko, V.*
AU  - Hinrichs, A.*
AU  - Kemter, E.*
AU  - Krause, S.*
AU  - Wanke, R.*
AU  - Arnold, G.J.*
AU  - Wess, G.*
AU  - Nagashima, H.*
AU  - Hrabě de Angelis, M.
AU  - Flenkenthaler, F.*
AU  - Kobelke, L.A.*
AU  - Bearzi, C.*
AU  - Rizzi, R.*
AU  - Bahr, A.*
AU  - Reese, S.*
AU  - Matiasek, K.*
AU  - Walter, M.C.*
AU  - Kupatt, C.*
AU  - Ziegler, S.*
AU  - Bartenstein, P.*
AU  - Fröhlich, T.*
AU  - Klymiuk, N.*
AU  - Blutke, A.
AU  - Wolf, E.*
C1  - 63638
C2  - 51462
CY  - Bidder Building, Station Rd, Histon, Cambridge Cb24 9lf, England
TI  - A scalable, clinically severe pig model for Duchenne muscular dystrophy.
JO  - Dis. Model. Mech.
VL  - 14
IS  - 12
PB  - Company Biologists Ltd
PY  - 2021
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Islet inflammation and cytokine production are implicated in pancreatic beta-cell dysfunction and diabetes pathogenesis. However, we lack therapeutics to protect the insulin-producing beta-cells from inflammatory damage. Closing this clinical gap requires the establishment of new disease models of islet inflammation to facilitate screening efforts aimed at identifying new protective agents. Here, we have developed a genetic model of Interleukin-1 beta (Il-1 beta)-driven islet inflammation in zebrafish, a vertebrate that allows for non-invasive imaging of beta-cells and in vivo drug discovery. Live imaging of immune cells and beta-cells in our model revealed dynamic migration, increased visitation and prolonged macrophage retention in the islet, together with robust activation of NF-kappa B signalling in beta-cells. We find that Il-1 beta-mediated inflammation does not cause beta-cell destruction but, rather, it impairs beta-cell function and identity. In vivo, beta-cells exhibit impaired glucose-stimulated calcium influx and reduced expression of genes involved in function and maturity. These defects are accompanied by alpha-cell expansion, glucose intolerance and hyperglycemia following a glucose challenge. Notably, we show that a medicinal plant derivative (wedelolactone) is capable of reducing the immune-cell infiltration while also ameliorating the hyperglycemic phenotype of our model. Importantly, these anti-diabetic properties in zebrafish are predictive of wedelolactone's efficacy in protecting rodent and human islets fromcytokine-induced apoptosis. Insummary, this newzebrafish model of diabetes opens a window to study the interactions between immune and beta-cells in vivo, while also allowing the identification of therapeutic agents for protecting beta-cells from inflammation.
AU  - Delgadillo-Silva, L.F.
AU  - Tsakmaki, A.*
AU  - Akhtar, N.*
AU  - Franklin, Z.J.*
AU  - Konantz, J.*
AU  - Bewick, G.A.*
AU  - Ninov, N.
C1  - 55407
C2  - 46351
CY  - Bidder Building, Station Rd, Histon, Cambridge Cb24 9lf, England
TI  - Modelling pancreatic beta-cell inflammation in zebrafish identifies the natural product wedelolactone for human islet protection.
JO  - Dis. Model. Mech.
VL  - 12
IS  - 1
PB  - Company Biologists Ltd
PY  - 2019
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Alongside the obesity epidemic, the prevalence of maternal diabetes is rising worldwide, and adverse effects on fetal development and metabolic disturbances in the offspring's later life have been described. To clarify whether metabolic programming effects are due to mild maternal hyperglycemia without confounding obesity, we investigated wild-type offspring of INSC93S transgenic pigs, which are a novel genetically modified large-animal model expressing mutant insulin (INS) C93S in pancreatic beta-cells. This mutation results in impaired glucose tolerance, mild fasting hyperglycemia and insulin resistance during late pregnancy. Compared with offspring from wildtype sows, piglets from hyperglycemic mothers showed impaired glucose tolerance and insulin resistance (homeostatic model assessment of insulin resistance: +3-fold in males; +4.4-fold in females) prior to colostrum uptake. Targeted metabolomics in the fasting and insulin-stimulated state revealed distinct alterations in the plasma metabolic profile of piglets from hyperglycemic mothers. They showed increased levels of acylcarnitines, gluconeogenic precursors such as alanine, phospholipids (in particular lysophosphatidylcholines) and a-aminoadipic acid, a potential biomarker for type 2 diabetes. These observations indicate that mild gestational hyperglycemia can cause impaired glucose tolerance, insulin resistance and associated metabolic alterations in neonatal offspring of a large-animal model born at a developmental maturation status comparable to human babies.
AU  - Renner, S.*
AU  - Martins, A.S.*
AU  - Streckel, E.*
AU  - Braun-Reichhart, C.*
AU  - Backman, M.*
AU  - Prehn, C.
AU  - Klymiuk, N.*
AU  - Bähr, A.*
AU  - Blutke, A.
AU  - Landbrecht-Schessl, C.*
AU  - Wünsch, A.*
AU  - Kessler, B.*
AU  - Kurome, M.*
AU  - Hinrichs, A.*
AU  - Koopmans, S.J.*
AU  - Krebs, S.*
AU  - Kemter, E.*
AU  - Rathkolb, B.
AU  - Nagashima, H.*
AU  - Blum, H.*
AU  - Ritzmann, M.*
AU  - Wanke, R.*
AU  - Aigner, B.*
AU  - Adamski, J.
AU  - Hrabě de Angelis, M.
AU  - Wolf, E.*
C1  - 56580
C2  - 47089
CY  - Bidder Building, Station Rd, Histon, Cambridge Cb24 9lf, England
TI  - Mild maternal hyperglycemia in INSC93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring.
JO  - Dis. Model. Mech.
VL  - 12
IS  - 8
PB  - Company Biologists Ltd
PY  - 2019
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as Idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive pulmonary Disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising.The Planar Cell Polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly due to the perinatal lethality of many PCP mouse mutant lines.Here we have investigated heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2(Lp/+) lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin modifying protein cofilin. In addition, we show that Vangl2(Lp/+) lungs exhibit many of the hallmarks of tissue damage including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in the lung disease, emphysema.In vitro, VANGL2 disruption impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking (a tissue damaging insult) on lung function. Finally, we show that that PCP genes VANGL2 and SCRIBBLE (SCRIB) are significantly downregulated in lung tissue from patients with emphysema.Our data reveals an important novel role for the PCP pathway in adult lung homeostasis and repair and sheds new light on the genetic factors which may modify destructive lung diseases such as emphysema.
AU  - Poobalasingam, T.*
AU  - Yates, L.L.*
AU  - Walker, S.A.*
AU  - Pereira, M.*
AU  - Gross, N.Y.*
AU  - Ali, A.*
AU  - Kolatsi-Joannou, M.*
AU  - Jarvelin, M.R.*
AU  - Pekkanen, J.*
AU  - Papakrivopoulou, E.*
AU  - Long, D.A.*
AU  - Griffiths, M.*
AU  - Wagner, D.E.
AU  - Königshoff, M.
AU  - Hind, M.*
AU  - Minelli, C.*
AU  - Lloyd, C.M.*
AU  - Dean, C.H.*
C1  - 50635
C2  - 42655
CY  - Cambridge
SP  - 409-423
TI  - Heterozygous Vangl2Looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair.
JO  - Dis. Model. Mech.
VL  - 10
IS  - 4
PB  - Company Of Biologists Ltd
PY  - 2017
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - MEIS1 is a developmental transcription factor linked to restless legs syndrome (RLS) in genome-wide association studies. RLS is a movement disorder leading to severe sleep reduction and with significant impact on the quality-of-life of patients. In genome-wide association studies, MEIS1 has consistently been the gene with the highest effect size and functional studies suggest a disease-relevant downregulation. Therefore, haploinsufficiency of Meis1 could be the most potential system for modeling RLS in animals. We used heterozygous Meis1 knock-out mice to study the effects of Meis1 haploinsufficiency on mouse behavioral and neurological phenotypes, and to relate the findings to human RLS. We exposed the Meis1-deficient mice to assays of motor, sensorimotor and cognitive ability and assessed the effect of a dopaminergic receptor 2/3 agonist commonly used in the treatment of RLS. The mutant mice showed a pattern of circadian hyperactivity, compatible with human RLS. Moreover, we discovered a replicable prepulse inhibition (PPI) deficit in the Meis1-deficient animals. In addition, these mice were hyposensitive to the PPI-reducing effect of the dopaminergic receptor agonist, highlighting a role of Meis1 in the dopaminergic system. Other reported phenotypes include enhanced social recognition at an older age that was not related to alterations in adult olfactory bulb neurogenesis previously shown to be implicated in this behavior. In conclusion, the Meis1-deficient mice fulfill some of the hallmarks of an RLS animal model, and revealed the role of Meis1 in sensorimotor gating and in the dopaminergic systems modulating it.
AU  - Salminen, A.V.
AU  - Garrett, L.
AU  - Schormair, B.
AU  - Rozman, J.
AU  - Giesert, F.
AU  - Niedermeier, K.M.
AU  - Becker, L.
AU  - Rathkolb, B.
AU  - Rácz, I.
AU  - Klingenspor, M.*
AU  - Klopstock, T.*
AU  - Wolf, E.*
AU  - Zimmer, A.*
AU  - Gailus-Durner, V.
AU  - Torres, M.*
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Wurst, W.
AU  - Hölter, S.M.
AU  - Winkelmann, J.
C1  - 51390
C2  - 43183
CY  - Cambridge
SP  - 981-991
TI  - Meis1 effects on motor phenotypes and the sensorimotor system in mice.
JO  - Dis. Model. Mech.
VL  - 10
IS  - 8
PB  - Company Of Biologists Ltd
PY  - 2017
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Plants and many lower organisms, but not mammals, express alternative oxidases (AOX) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell-lines, Drosophila disease models and, most recently, in the mouse, where multiple, lentivector-AOX transgenes conferred substantial expression in specific tissues. Here we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOXRosa26 mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello, whilst animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOXRosa26 mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.
AU  - Szibor, M.*
AU  - Dhandapani, P.K.*
AU  - Dufour, E.*
AU  - Holmström, K.M.*
AU  - Zhuang, Y.*
AU  - Salwig, I.*
AU  - Wittig, I.*
AU  - Heidler, J.*
AU  - Gizatullina, Z.*
AU  - Gainutdinov, T.*
AU  - German Mouse Clinic Consortium (Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - Aguilar-Pimentel, J.A.
AU  - Schmidt-Weber, C.B.
AU  - Becker, L.
AU  - Adler, T.
AU  - Treise, I.
AU  - Horsch, M.
AU  - Beckers, J.
AU  - Moreth, K.
AU  - Garrett, L.
AU  - Hölter, S.M.
AU  - Zimprich, A.
AU  - Wurst, W.
AU  - Hans, W.
AU  - Amarie, O.V.
AU  - Graw, J.
AU  - Rozman, J.
AU  - Calzada-Wack, J.
AU  - Da Silva-Buttkus, P.
AU  - Neff, F.
AU  - Rácz, I.
AU  - Rathkolb, B.
AU  - Östereicher, M.A.
AU  - Steinkamp, R.
AU  - Lengger, C.
AU  - Maier, H.
AU  - Stoeger, C.
AU  - Leuchtenberger, S.)
AU  - Nandania, J.*
AU  - Velagapudi,V.*
AU  - Wietelmann, A.*
AU  - Rustin, P.*
AU  - Gellerich, F.N.*
AU  - Jacobs, H.T.*
AU  - Braun, T.*
C1  - 50260
C2  - 42205
CY  - Cambridge
SP  - 163-171
TI  - Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology.
JO  - Dis. Model. Mech.
VL  - 10
IS  - 2
PB  - Company Of Biologists Ltd
PY  - 2017
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - The alveolar epithelium represents a major site of tissue destruction during lung injury. It consists of alveolar epithelial type I (ATI) and type II (ATII) cells. ATII cells are capable of self-renewal and exert progenitor function for ATI cells upon alveolar epithelial injury. Cell differentiation pathways enabling this plasticity and allowing for proper repair, however, are poorly understood. Here, we applied proteomics, expression analysis, and functional studies in primary murine ATII cells to identify novel proteins and molecular mechanisms involved in alveolar epithelial plasticity. Mass spectrometry of cultured ATII cells revealed a reduction of carbonyl reductase 2 (CBR2) and an increase in enolase 1 (ENO1) and protein disulfide isomerase associated 3 (PDIA3) protein expression during ATII to ATI cell trans-differentiation. This was accompanied by increased Wnt/β-catenin signaling, as analyzed by qRT-PCR and immunoblotting. Notably, ENO1 and PDIA3, along with T1α, exhibited decreased protein expression upon pharmacological and molecular Wnt/β-catenin inhibition in cultured ATII cells, while CBR2 levels were stabilized. Moreover, we analyzed primary ATII cells from bleomycin-induced lung injury, a model exhibiting activated Wnt/β-catenin signaling in vivo. We observed reduced CBR2 significantly correlating with SFTPC, whereas ENO1 and PDIA3 along with T1α were increased in injured ATII cells. Finally, siRNA-mediated knockdown of ENO1, as well as PDIA3, in primary ATII cells led to reduced T1α expression, indicating diminished cell trans-differentiation. Our data thus identified novel proteins involved in ATII to ATI cell trans-differentiation and suggest a Wnt/β-catenin-driven functional role of ENO1 and PDIA3 in alveolar epithelial cell plasticity in lung injury and repair.
AU  - Mutze, K.
AU  - Vierkotten, S.
AU  - Milosevic, J.*
AU  - Eickelberg, O.
AU  - Königshoff, M.
C1  - 45095
C2  - 37240
CY  - Cambridge
SP  - 877-890
TI  - Enolase 1 and protein disulfide isomerase associated 3 regulate Wnt/β-catenin driven trans-differentiation of murine alveolar epithelial cells.
JO  - Dis. Model. Mech.
VL  - 8
IS  - 8
PB  - Company Of Biologists Ltd
PY  - 2015
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Neural damage is a devastating outcome of physical trauma. The glia are one of the main effectors of neuronal repair in the nervous system, but the dynamic interactions between peripheral neurons and Schwann cells during injury and regeneration remain incompletely characterized. Here, we combine laser microsurgery, genetic analysis, high-resolution intravital imaging and lattice light-sheet microscopy to study the interaction between Schwann cells and sensory neurons in a zebrafish model of neurotrauma. We found that chronic denervation by neuronal ablation leads to Schwann-cell death, whereas acute denervation by axonal severing does not affect the overall complexity and architecture of the glia. Neuronal-circuit regeneration begins when Schwann cells extend bridging processes to close the injury gap. Regenerating axons grow faster and directionally after the physiological clearing of distal debris by the Schwann cells. This might facilitate circuit repair by ensuring that axons are guided through unoccupied spaces within bands of Büngner towards their original peripheral target. Accordingly, in the absence of Schwann cells, regenerating axons are misrouted, impairing the re-innervation of sensory organs. Our results indicate that regenerating axons use haptotaxis as a directional cue during the reconstitution of a neural circuit. These findings have implications for therapies aimed at neurorepair, which will benefit from preserving the architecture of the peripheral glia during periods of denervation.
AU  - Xiao, Y.
AU  - Faucherre, A.*
AU  - Pola-Morell, L.*
AU  - Heddleston, J.M.*
AU  - Liu, T.L.*
AU  - Chew, T.L.*
AU  - Sato, F.*
AU  - Sehara-Fujisawa, A.*
AU  - Kawakami, K.*
AU  - López-Schier, H.
C1  - 45094
C2  - 37241
CY  - Cambridge
SP  - 553-564
TI  - High-resolution live imaging reveals axon-glia interactions during peripheral nerve injury and repair in zebrafish.
JO  - Dis. Model. Mech.
VL  - 8
IS  - 6
PB  - Company Of Biologists Ltd
PY  - 2015
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Identifying genes that are important for embryo development is a crucial first step towards understanding their many functions in driving the ordered growth, differentiation and organogenesis of embryos. It can also shed light on the origins of developmental disease and congenital abnormalities. Current international efforts to examine gene function in the mouse provide a unique opportunity to pinpoint genes that are involved in embryogenesis, owing to the emergence of embryonic lethal knockout mutants. Through internationally coordinated efforts, the International Knockout Mouse Consortium (IKMC) has generated a public resource of mouse knockout strains and, in April 2012, the International Mouse Phenotyping Consortium (IMPC), supported by the EU InfraCoMP programme, convened a workshop to discuss developing a phenotyping pipeline for the investigation of embryonic lethal knockout lines. This workshop brought together over 100 scientists, from 13 countries, who are working in the academic and commercial research sectors, including experts and opinion leaders in the fields of embryology, animal imaging, data capture, quality control and annotation, high-throughput mouse production, phenotyping, and reporter gene analysis. This article summarises the outcome of the workshop, including (1) the vital scientific importance of phenotyping embryonic lethal mouse strains for basic and translational research; (2) a common framework to harmonise international efforts within this context; (3) the types of phenotyping that are likely to be most appropriate for systematic use, with a focus on 3D embryo imaging; (4) the importance of centralising data in a standardised form to facilitate data mining; and (5) the development of online tools to allow open access to and dissemination of the phenotyping data.
AU  - Adams, D.*
AU  - Baldock, R.*
AU  - Bhattacharya, S.*
AU  - Copp, A.J.*
AU  - Dickinson, M.*
AU  - Greene, N.D.E.*
AU  - Henkelmann, M.*
AU  - Justice, M.*
AU  - Mohun, T.*
AU  - Murray, S.A.*
AU  - Pauws, E.*
AU  - Raess, M.
AU  - Rossant, J.*
AU  - Weaver, T.*
AU  - West, D.*
C1  - 24839
C2  - 31706
SP  - 571-579
TI  - Bloomsbury report on mouse embryo phenotyping: Recommendations from the IMPC workshop on embryonic lethal screening.
JO  - Dis. Model. Mech.
VL  - 6
IS  - 3
PB  - Company of Biologists Ltd.
PY  - 2013
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - The ideal anti-obesity drug would produce sustained weight loss with minimal side effects. The mechanisms that regulate energy balance have substantial built-in redundancy, overlap considerably with other physiological functions, and are influenced by social, hedonic and psychological factors that limit the effectiveness of pharmacological interventions. It is therefore unsurprising that anti-obesity drug discovery programmes have been littered with false starts, failures in clinical development, and withdrawals due to adverse effects that were not fully appreciated at the time of launch. Drugs that target pathways in metabolic tissues, such as adipocytes, liver and skeletal muscle, have shown potential in preclinical studies but none has yet reached clinical development. Recent improvements in the understanding of peptidergic signalling of hunger and satiety from the gastrointestinal tract mediated by ghrelin, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, have opened up new possibilities. Although some have now reached clinical development, it is uncertain whether they will meet the strict regulatory hurdles required for licensing of an anti-obesity drug. However, GLP-1 receptor agonists have already succeeded in diabetes treatment and, owing to their attractive body-weight-lowering effects in humans, will perhaps also pave the way for other anti-obesity agents. To succeed in developing drugs that control body weight to the extent seen following surgical intervention, it seems obvious that a new paradigm is needed. In other therapeutic arenas, such as diabetes and hypertension, lower doses of multiple agents targeting different pathways often yield better results than strategies that modify one pathway alone. Some combination approaches using peptides and small molecules have now reached clinical trials, although recent regulatory experience suggests that large challenges lie ahead. In future, this polytherapeutic strategy could possibly rival surgery in terms of efficacy, safety and sustainability of weight loss.
AU  - Rodgers, R.J.*
AU  - Tschöp, M.H.
AU  - Wilding, J.P.H.*
C1  - 10631
C2  - 30319
SP  - 621-626
TI  - Anti-obesity drugs: Past, present and future.
JO  - Dis. Model. Mech.
VL  - 5
IS  - 5
PB  - Company of Biologists Ltd.
PY  - 2012
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - Obesity and concomitant comorbidities have emerged as public health problems of the first order. For instance, obese individuals have an increased risk for kidney cancer. However, direct mechanisms linking obesity with kidney cancer remain elusive. We hypothesized that diet-induced obesity (DIO) promotes renal carcinogenesis by inducing an inflammatory and tumor-promoting microenvironment. We compared chow-fed lean Wistar rats with those that were sensitive (DIOsens) or partially resistant (DIOres) to DIO to investigate the impact of body adiposity versus dietary nutrient overload in the development of renal preneoplasia and activation of tumor-promoting signaling pathways. Our data clearly show a correlation between body adiposity, the severity of nephropathy, and the total number and incidence of preneoplastic renal lesions. However, similar plasma triglyceride, plasma free fatty acid and renal triglyceride levels were found in chow-fed, DIOres and DIOsens rats, suggesting that lipotoxicity is not a critical contributor to the renal pathology. Obesity-related nephropathy was further associated with regenerative cell proliferation, monocyte infiltration and higher renal expression of monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-6, IL-6 receptor and leptin receptor. Accordingly, we observed increased signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) phosphorylation in tubules with preneoplastic phenotypes. In summary, our results demonstrate that high body adiposity induces an inflammatory and proliferative microenvironment in rat kidneys that promotes the development of preneoplastic lesions, potentially via activation of the STAT3 and mTOR signaling pathways.
AU  - Stemmer, K.
AU  - Perez-Tilve, D.*
AU  - Ananthakrishnan, G.*
AU  - Bort, A.*
AU  - Seeley, R.J.*
AU  - Tschöp, M.H.
AU  - Dietrich, D.R.*
AU  - Pfluger, P.T.
C1  - 10639
C2  - 30318
SP  - 627-635
TI  - High-fat-diet-induced obesity causes an inflammatory and tumor-promoting microenvironment in the rat kidney.
JO  - Dis. Model. Mech.
VL  - 5
IS  - 5
PB  - Company of Biologists Ltd.
PY  - 2012
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - The mediobasal hypothalamic arcuate nucleus (ARC), with its relatively 'leaky' blood-brain barrier that allows more circulating molecules to enter the brain, has emerged as a key sensor of blood-borne signals. In both the ARC and white adipose tissue (WAT), consumption of a high-fat diet (HFD) rapidly induces infiltration of microglia (ARC) or macrophages (WAT). Animals with HFD-induced obesity (DIO) and insulin resistance additionally accumulate B cells in WAT, increasing the local production of pathogenic antibodies. We therefore investigated whether DIO mice or genetically obese ob/ob mice have increased IgG in the ARC, analogous to the recent observations in WAT. Following 16 weeks of exposure to a HFD, wild-type (WT) mice had significantly increased IgG-immunoreactivity (ir) signaling that was specific to the ARC and was exclusively concentrated in microglia. By contrast, IgG-ir of age-matched obese ob/ob mice fed standard chow had ARC IgG levels comparable with those in chow-fed WT control mice. However, following 2 weeks of HFD exposure, ob/ob mice also had a significant increase of IgG-ir in the ARC. In summary, our findings reveal a novel pathophysiological phenomenon, specific for the hypothalamic ARC, that is induced by exposure to a HFD and can be enhanced, but not caused, by genetic obesity.
AU  - Yi, C.-X.
AU  - Tschöp, M.H.
AU  - Woods, S.C.*
AU  - Hofmann, S.M.
C1  - 8321
C2  - 30056
SP  - 686-690
TI  - High-fat-diet exposure induces IgG accumulation in hypothalamic microglia.
JO  - Dis. Model. Mech.
VL  - 5
IS  - 5
PB  - COMPANY OF BIOLOGISTS LTD
PY  - 2012
SN  - 1754-8403
ER  - 

TY  - JOUR
AB  - One of the 'side effects' of our modern lifestyle is a range of metabolic diseases: the incidence of obesity, type 2 diabetes and associated cardiovascular diseases has grown to pandemic proportions. This increase, which shows no sign of reversing course, has occurred despite education and new treatment options, and is largely due to a lack of knowledge about the precise pathology and etiology of metabolic disorders. Accumulating evidence suggests that the communication pathways linking the brain, gut and adipose tissue might be promising intervention points for metabolic disorders. To maintain energy homeostasis, the brain must tightly monitor the peripheral energy state. This monitoring is also extremely important for the brain's survival, because the brain does not store energy but depends solely on a continuous supply of nutrients from the general circulation. Two major groups of metabolic inputs inform the brain about the peripheral energy state: short-term signals produced by the gut system and long-term signals produced by adipose tissue. After central integration of these inputs, the brain generates neuronal and hormonal outputs to balance energy intake with expenditure. Miscommunication between the gut, brain and adipose tissue, or the degradation of input signals once inside the brain, lead to the brain misunderstanding the peripheral energy state. Under certain circumstances, the brain responds to this miscommunication by increasing energy intake and production, eventually causing metabolic disorders. This poster article overviews current knowledge about communication pathways between the brain, gut and adipose tissue, and discusses potential research directions that might lead to a better understanding of the mechanisms underlying metabolic disorders.
AU  - Yi, C.X.*
AU  - Tschöp, M.H.
C1  - 58397
C2  - 0
SP  - 583-587
TI  - Brain-gut-adipose-tissue communication pathways at a glance.
JO  - Dis. Model. Mech.
VL  - 5
IS  - 5
PY  - 2012
SN  - 1754-8403
ER  -