Publications
224 results found
Haas MA, Bell D, Slender A, et al., 2013, Alterations to Dendritic Spine Morphology, but Not Dendrite Patterning, of Cortical Projection Neurons in Tc1 and Ts1Rhr Mouse Models of Down Syndrome, PLOS ONE, Vol: 8, ISSN: 1932-6203
Down Syndrome (DS) is a highly prevalent developmental disorder, affecting 1/700 births. Intellectual disability, whichaffects learning and memory, is present in all cases and is reflected by below average IQ. We sought to determine whetherdefective morphology and connectivity in neurons of the cerebral cortex may underlie the cognitive deficits that have beendescribed in two mouse models of DS, the Tc1 and Ts1Rhr mouse lines. We utilised in utero electroporation to label a cohortof future upper layer projection neurons in the cerebral cortex of developing mouse embryos with GFP, and then examinedneuronal positioning and morphology in early adulthood, which revealed no alterations in cortical layer position ormorphology in either Tc1 or Ts1Rhr mouse cortex. The number of dendrites, as well as dendrite length and branching wasnormal in both DS models, compared with wildtype controls. The sites of projection neuron synaptic inputs, dendriticspines, were analysed in Tc1 and Ts1Rhr cortex at three weeks and three months after birth, and significant changes in spinemorphology were observed in both mouse lines. Ts1Rhr mice had significantly fewer thin spines at three weeks of age. Atthree months of age Tc1 mice had significantly fewer mushroom spines - the morphology associated with establishedsynaptic inputs and learning and memory. The decrease in mushroom spines was accompanied by a significant increase inthe number of stubby spines. This data suggests that dendritic spine abnormalities may be a more important contributor tocognitive deficits in DS models, rather than overall neuronal architecture defects.
Choong XY, Raha A, Tybulewicz V, et al., 2013, P1–106: Using primary neurons from transgenic mice to identify genes on human chromosome 21 influencing Alzheimer's neuropathology, Alzheimer's & Dementia, Vol: 9, ISSN: 1552-5260
Gribble SM, Wiseman FK, Clayton S, et al., 2013, Massively parallel sequencing reveals the complex structure of an irradiated human chromosome on a mouse background in the Tc1 model of down syndrome, PLoS ONE, Vol: 8, ISSN: 1932-6203
Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439.
Schweighoffer E, Vanes L, Nys J, et al., 2013, The BAFF Receptor Transduces Survival Signals by Co-opting the B Cell Receptor Signaling Pathway, IMMUNITY, Vol: 38, Pages: 475-488, ISSN: 1074-7613
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- Citations: 151
Ahmed MM, Dhanasekaran AR, Tong S, et al., 2013, Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 1709-1724, ISSN: 0964-6906
Tc1 mouse model of Down syndrome (DS) is functionally trisomic for ∼120 human chromosome 21 (HSA21) classical protein-coding genes. Tc1 mice display features relevant to the DS phenotype, including abnormalities in learning and memory and synaptic plasticity. To determine the molecular basis for the phenotypic features, the levels of 90 phosphorylation-specific and phosphorylation-independent proteins were measured by Reverse Phase Protein Arrays in hippocampus and cortex, and 64 in cerebellum, of Tc1 mice and littermate controls. Abnormal levels of proteins involved in MAP kinase, mTOR, GSK3B and neuregulin signaling were identified in trisomic mice. In addition, altered correlations among the levels of N-methyl-D-aspartate (NMDA) receptor subunits and the HSA21 proteins amyloid beta (A4) precursor protein (APP) and TIAM1, and between immediate early gene (IEG) proteins and the HSA21 protein superoxide dismutase-1 (SOD1) were found in the hippocampus of Tc1 mice, suggesting altered stoichiometry among these sets of functionally interacting proteins. Protein abnormalities in Tc1 mice were compared with the results of a similar analysis of Ts65Dn mice, a DS mouse model that is trisomic for orthologs of 50 genes trisomic in the Tc1 plus an additional 38 HSA21 orthologs. While there are similarities, abnormalities unique to the Tc1 include increased levels of the S100B calcium-binding protein, mTOR proteins RAPTOR and P70S6, the AMP-kinase catalytic subunit AMPKA, the IEG proteins FBJ murine osteosarcoma viral oncogene homolog (CFOS) and activity-regulated cytoskeleton-associated protein (ARC), and the neuregulin 1 receptor ERBB4. These data identify novel perturbations, relevant to neurological function and to some seen in Alzheimer's disease, that may occur in the DS brain, potentially contributing to phenotypic features and influencing drug responses.
Ksionda O, Saveliev A, Koechl R, et al., 2012, Mechanism and function of Vav1 localisation in TCR signalling, JOURNAL OF CELL SCIENCE, Vol: 125, Pages: 5302-5314, ISSN: 0021-9533
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- Citations: 22
Roth S, Bergmann H, Neumann K, et al., 2012, Vav proteins mediate Syk kinase-coupled C-type lectin receptor induced innate immune responses, European Congress of Immunology, Publisher: WILEY-BLACKWELL, Pages: 30-30, ISSN: 0019-2805
Grizenkova J, Akhtar S, Hummerich H, et al., 2012, Overexpression of the <i>Hspa13</i> (<i>Stch</i>) gene reduces prion disease incubation time in mice, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 13722-13727, ISSN: 0027-8424
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- Citations: 14
Haubert D, Li J, Saveliev A, et al., 2012, Vav1 GEF activity is required for T cell mediated allograft rejection, TRANSPLANT IMMUNOLOGY, Vol: 26, Pages: 212-219, ISSN: 0966-3274
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- Citations: 6
Sheppard O, Plattner F, Rubin A, et al., 2012, Altered regulation of tau phosphorylation in a mouse model of down syndrome aging, NEUROBIOLOGY OF AGING, Vol: 33, ISSN: 0197-4580
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- Citations: 41
Vidaki M, Tivodar S, Doulgeraki K, et al., 2012, Rac1-Dependent Cell Cycle Exit of MGE Precursors and GABAergic Interneuron Migration to the Cortex, CEREBRAL CORTEX, Vol: 22, Pages: 680-692, ISSN: 1047-3211
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- Citations: 37
Finney BA, Schweighoffer E, Navarro-Nunez L, et al., 2012, CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development, BLOOD, Vol: 119, Pages: 1747-1756, ISSN: 0006-4971
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- Citations: 98
Sheppard O, Wiseman FK, Ruparelia A, et al., 2012, Mouse models of aneuploidy, The Scientific World Journal, Vol: 2012, ISSN: 1537-744X
Abnormalities of chromosome copy number are called aneuploidies and make up a large health load on the human population. Many aneuploidies are lethal because the resulting abnormal gene dosage is highly deleterious. Nevertheless, some whole chromosome aneuploidies can lead to live births. Alterations in the copy number of sections of chromosomes, which are also known as segmental aneuploidies, are also associated with deleterious effects. Here we examine how aneuploidy of whole chromosomes and segmental aneuploidy of chromosomal regions are modeled in the mouse. These models provide a whole animal system in which we aim to investigate the complex phenotype-genotype interactions that arise from alteration in the copy number of genes. Although our understanding of this subject is still in its infancy, already research in mouse models is highlighting possible therapies that might help alleviate the cognitive effects associated with changes in gene number. Thus, creating and studying mouse models of aneuploidy and copy number variation is important for understanding what it is to be human, in both the normal and genomically altered states.
Devoy A, Bunton-Stasyshyn RKA, Tybulewicz VLJ, et al., 2012, Genomically humanized mice: technologies and promises, NATURE REVIEWS GENETICS, Vol: 13, Pages: 14-20, ISSN: 1471-0056
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- Citations: 69
Singleton KL, Gosh M, Dandekar RD, et al., 2011, Itk Controls the Spatiotemporal Organization of T Cell Activation, SCIENCE SIGNALING, Vol: 4, ISSN: 1945-0877
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- Citations: 43
Lana-Elola E, Watson-Scales SD, Fisher EMC, et al., 2011, Down syndrome: searching for the genetic culprits, DISEASE MODELS & MECHANISMS, Vol: 4, Pages: 586-595, ISSN: 1754-8403
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- Citations: 73
Cleary JO, Wiseman FK, Norris FC, et al., 2011, Structural correlates of active-staining following magnetic resonance microscopy in the mouse brain, NEUROIMAGE, Vol: 56, Pages: 974-983, ISSN: 1053-8119
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- Citations: 25
da Gloria Sousa M, Reid DM, Schweighoffer E, et al., 2011, Restoration of Pattern Recognition Receptor Costimulation to Treat Chromoblastomycosis, a Chronic Fungal Infection of the Skin, CELL HOST & MICROBE, Vol: 9, Pages: 436-443, ISSN: 1931-3128
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- Citations: 112
Duchon A, Pothion S, Brault V, et al., 2011, The telomeric part of the human chromosome 21 from <i>Cstb</i> to <i>Prmt2</i> is not necessary for the locomotor and short-term memory deficits observed in the Tc1 mouse model of Down syndrome, BEHAVIOURAL BRAIN RESEARCH, Vol: 217, Pages: 271-281, ISSN: 0166-4328
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- Citations: 25
Faroudi M, Hons M, Zachacz A, et al., 2010, Critical roles for Rac GTPases in T-cell migration to and within lymph nodes, BLOOD, Vol: 116, Pages: 5536-5547, ISSN: 0006-4971
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- Citations: 65
Anderson KE, Chessa TAM, Davidson K, et al., 2010, PtdIns3P and Rac direct the assembly of the NADPH oxidase on a novel, pre-phagosomal compartment during FcR-mediated phagocytosis in primary mouse neutrophils, BLOOD, Vol: 116, Pages: 4978-4989, ISSN: 0006-4971
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- Citations: 48
Haas MA, Fisher EMC, Tybulewicz VLJ, et al., 2010, Cortical projection neuron dendrite morphology in the Tc1 mouse model of Down Syndrome, INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE, Vol: 28, Pages: 706-706, ISSN: 0736-5748
Wiseman FK, Sheppard O, Linehan JM, et al., 2010, Generation of a panel of antibodies against proteins encoded on human chromosome 21., Journal of Negative Results in Biomedicine, Vol: 9, ISSN: 1477-5751
BACKGROUND: Down syndrome (DS) is caused by trisomy of all or part of chromosome 21. To further understanding of DS we are working with a mouse model, the Tc1 mouse, which carries most of human chromosome 21 in addition to the normal mouse chromosome complement. This mouse is a model for human DS and recapitulates many of the features of the human syndrome such as specific heart defects, and cerebellar neuronal loss. The Tc1 mouse is mosaic for the human chromosome such that not all cells in the model carry it. Thus to help our investigations we aimed to develop a method to identify cells that carry human chromosome 21 in the Tc1 mouse. To this end, we have generated a panel of antibodies raised against proteins encoded by genes on human chromosome 21 that are known to be expressed in the adult brain of Tc1 mice RESULTS: We attempted to generate human specific antibodies against proteins encoded by human chromosome 21. We selected proteins that are expressed in the adult brain of Tc1 mice and contain regions of moderate/low homology with the mouse ortholog. We produced antibodies to seven human chromosome 21 encoded proteins. Of these, we successfully generated three antibodies that preferentially recognise human compared with mouse SOD1 and RRP1 proteins on western blots. However, these antibodies did not specifically label cells which carry a freely segregating copy of Hsa21 in the brains of our Tc1 mouse model of DS. CONCLUSIONS: Although we have successfully isolated new antibodies to SOD1 and RRP1 for use on western blots, in our hands these antibodies have not been successfully used for immunohistochemistry studies. These antibodies are freely available to other researchers. Our data high-light the technical difficulty of producing species-specific antibodies for both western blotting and immunohistochemistry.
De Vita S, Canzonetta C, Mulligan C, et al., 2010, Trisomic dose of several chromosome 21 genes perturbs haematopoietic stem and progenitor cell differentiation in Down's syndrome., Oncogene, Vol: 29, Pages: 6102-6114, ISSN: 0950-9232
Children with Down's syndrome (DS) have 20-50-fold higher incidence of all leukaemias (lymphoid and myeloid), for reasons not understood. As incidence of many solid tumours is much lower in DS, we speculated that disturbed early haematopoietic differentiation could be the cause of increased leukaemia risk. If a common mechanism is behind the risk of both major leukaemia types, it would have to arise before the bifurcation to myeloid and lymphoid lineages. Using the transchromosomic system (mouse embryonic stem cells (ESCs)) bearing an extra human chromosome 21 (HSA21)) we analyzed the early stages of haematopoietic commitment (mesodermal colony formation) in vitro. We observed that trisomy 21 (T21) causes increased production of haemogenic endothelial cells, haematopoietic stem cell precursors and increased colony forming potential, with significantly increased immature progenitors. Transchromosomic colonies showed increased expression of Gata-2, c-Kit and Tie-2. A panel of partial T21 ESCs allowed us to assign these effects to HSA21 sub-regions, mapped by 3.5 kbp-resolution tiling arrays. The Gata-2 increase on one side, and c-Kit and Tie-2 increases on the other, could be attributed to two different, non-overlapping HSA21 regions. Using human-specific small interfering RNA silencing, we could demonstrate that an extra copy of RUNX1, but not ETS-2 or ERG, causes an increase in Tie-2/c-Kit levels. Finally, we detected significantly increased levels of RUNX1, C-KIT and PU.1 in human foetal livers with T21. We conclude that overdose of more than one HSA21 gene contributes to the disturbance of early haematopoiesis in DS, and that one of the contributors is RUNX1. As the observed T21-driven hyperproduction of multipotential immature precursors precedes the bifurcation to lymphoid and myeloid lineages, we speculate that this could create conditions of increased chance for acquisition of pre-leukaemogenic rearrangements/mutations in both lymphoid and myeloid linea
Dunlevy L, Bennett M, Slender A, et al., 2010, Down's syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse, CARDIOVASCULAR RESEARCH, Vol: 88, Pages: 287-295, ISSN: 0008-6363
AimsCardiac malformations are prevalent in trisomies of human chromosome 21 [Down's syndrome (DS)], affecting normal chamber separation in the developing heart. Efforts to understand the aetiology of these defects have been severely hampered by the absence of an accurate mouse model. Such models have proved challenging to establish because synteny with human chromosome Hsa21 is distributed across three mouse chromosomes. None of those engineered so far accurately models the full range of DS cardiac phenotypes, in particular the profound disruptions resulting from atrioventricular septal defects (AVSDs). Here, we present analysis of the cardiac malformations exhibited by embryos of the transchromosomic mouse line Tc(Hsa21)1TybEmcf (Tc1) which contains more than 90% of chromosome Hsa21 in addition to the normal diploid mouse genome.Methods and resultsUsing high-resolution episcopic microscopy and three-dimensional (3D) modelling, we show that Tc1 embryos exhibit many of the cardiac defects found in DS, including balanced AVSD with single and separate valvar orifices, membranous and muscular ventricular septal defects along with outflow tract and valve leaflet abnormalities. Frequencies of cardiac malformations (ranging from 38 to 55%) are dependent on strain background. In contrast, no comparable cardiac defects were detected in embryos of the more limited mouse trisomy model, Dp(16Cbr1-ORF9)1Rhr (Ts1Rhr), indicating that trisomy of the region syntenic to the Down's syndrome critical region, including the candidate genes DSCAM and DYRK1A, is insufficient to yield DS cardiac abnormalities.ConclusionThe Tc1 mouse line provides a suitable model for studying the underlying genetic causes of the DS AVSD cardiac phenotype.
Reynolds LE, Watson AR, Baker M, et al., 2010, Tumour angiogenesis is reduced in the Tc1 mouse model of Down's syndrome, Nature, Vol: 465, Pages: 813-817, ISSN: 0028-0836
Down’s syndrome (DS) is a genetic disorder caused by full or partial trisomy of human chromosome 21 and presents with many clinical phenotypes including a reduced incidence of solid tumours. Recent work with the Ts65Dn model of DS, which has orthologues of about 50% of the genes on chromosome 21 (Hsa21), has indicated that three copies of the ETS2 or DS candidate region 1 (DSCR1) genes (a previously known suppressor of angiogenesis5) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses roughly 81% of Hsa21 genes but not the human DSCR1 region. We transplanted B16F0 and Lewis lung carcinoma tumour cells into Tc1 mice and showed that growth of these tumours was substantially reduced compared with wild-type littermate controls. Furthermore, tumour angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS1and ERG) and novel endothelial cell-specific genes, never previously shown to be involved in angiogenesis (JAM-B and PTTG1IP), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis, explaining the reduced tumour growth in DS. Furthermore, we expect that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will permit the identification of other endothelium-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients.
Mocsai A, Ruland J, Tybulewicz VLJ, 2010, The SYK tyrosine kinase: a crucial player in diverse biological functions, NATURE REVIEWS IMMUNOLOGY, Vol: 10, Pages: 387-402, ISSN: 1474-1733
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- Citations: 898
Alford KA, Slender A, Vanes L, et al., 2010, Perturbed hematopoiesis in the Tc1 mouse model of Down syndrome, BLOOD, Vol: 115, Pages: 2928-2937, ISSN: 0006-4971
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- Citations: 46
Henderson RB, Grys K, Vehlow A, et al., 2010, A novel Rac-dependent checkpoint in B cell development controls entry into the splenic white pulp and cell survival, The Journal of Cell Biology, Vol: 189, Pages: i1-i1, ISSN: 0021-9525
Henderson RB, Grys K, Vehlow A, et al., 2010, A novel Rac-dependent checkpoint in B cell development controls entry into the splenic white pulp and cell survival, Journal of Experimental Medicine, Vol: 207, Pages: 837-853, ISSN: 0022-1007
Rac1 and Rac2 GTPases transduce signals from multiple receptors leading to cell migration, adhesion, proliferation, and survival. In the absence of Rac1 and Rac2, B cell development is arrested at an IgD− transitional B cell stage that we term transitional type 0 (T0). We show that T0 cells cannot enter the white pulp of the spleen until they mature into the T1 and T2 stages, and that this entry into the white pulp requires integrin and chemokine receptor signaling and is required for cell survival. In the absence of Rac1 and Rac2, transitional B cells are unable to migrate in response to chemokines and cannot enter the splenic white pulp. We propose that loss of Rac1 and Rac2 causes arrest at the T0 stage at least in part because transitional B cells need to migrate into the white pulp to receive survival signals. Finally, we show that in the absence of Syk, a kinase that transduces B cell antigen receptor signals required for positive selection, development is arrested at the same T0 stage, with transitional B cells excluded from the white pulp. Thus, these studies identify a novel developmental checkpoint that coincides with B cell positive selection.
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