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  • 18th International Mouse Genome Conference (2004)
    HUNTINGTON S DISEASE MODIFIERS IN THE MOUSE Acevedo A 1 Chrobot N 1 Rubinsztein DC 2 Brown SD 1 1 MRC Mammalian Genetics Unit Harwell United Kingdom 2 Cambridge Institute for Medical Research Cambridge United Kingdom Huntington s disease HD is an autosomal dominant progressive fatal neurodegenerative disorder caused by an expanded polyglutamine tract PolyQ in exon one of the HD gene Up to 70 of the variance in age of onset can be accounted for by an inverse relationship with polyQ repeat number The residual variance is likely to be mediated by environmental and genetic factors modifiers In order to identify dominant modifier genes for HD we have initiated an N ethyl N nitrosourea ENU mutagenesis screen with a mouse model of HD First we carried out extensive behavioural characterisation of two HD transgenic mouse models R6 1 and N171 82Q in order to select the one most suitable strain and to determine baseline phenotypes Both lines show early signs of disease including tremors weight loss and motor deficits However N171 82Q strain has more rapid disease progression and better fertility so it was chosen for the modifier screen We injected BALB c males 2 x 100mg kg ENU

    Original URL path: http://www.imgs.org/Archive/abstracts/2004abstracts/abs/file83.shtml (2016-02-17)
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  • 18th International Mouse Genome Conference (2004)
    of receptor tyrosine kinases including the insulin like growth factor type 1 Igf1r and insulin Insr receptors Here we address the physiological relevance of these biochemical interactions Genetic tests indicate that the effects of Grb10 on growth are essentially independent of IGF signalling On the other hand Grb10 interacts with Insr to control growth during embryogenesis in a highly organ specific manner and post natally to modulate glucose homeostasis Thus

    Original URL path: http://www.imgs.org/Archive/abstracts/2004abstracts/abs/file84.shtml (2016-02-17)
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  • 18th International Mouse Genome Conference (2004)
    Notch family in a ligand receptor like manner The Delta Notch signal transduction pathway is well conserved and plays a central role in mediating cell to cell communication regulating the determination of various cell fates during development Disruption of the Delta1 gene implies alteration of early embryonic development followed by embrionic lethality Hrabé de Angelis et al 1997 Moreover recent studies indicate that the Delta Notch pathway belongs to a

    Original URL path: http://www.imgs.org/Archive/abstracts/2004abstracts/abs/file85.shtml (2016-02-17)
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  • 18th International Mouse Genome Conference (2004)
    Smith FM 1 Charalambous M 2 Koumanov F 1 Garfield A 1 Ward A 1 1 Centre for Regenerative Medicine University of Bath Bath United Kingdom 2 Centre for Diabetes and Endocrinology Division of Medicine London United Kingdom Growth Factor Receptor bound protein 10 Grb10 is a member of the Grb7 family of SH2 domain containing adaptor proteins Murine Grb10 is maternally expressed located on chromosome 11 and uniparental disomy UPD of this region results in reciprocal growth phenotypes Grb10 has been shown to associate in vitro with a number of tyrosine kinase receptors including Igf1r and Insr although its function and signalling remain unclear Mice with disruption of the Grb10 locus were generated termed Grb10 D 2 4 to characterise the physiological role of this signalling protein Maternal transmission of Grb10 D 2 4 resulted in intrauterine and post natal growth enhancement with disproportionate effects on organ size and increased liver glycogen Despite Grb10 expression being reminiscent of the Igf2 expression pattern during development our findings indicate that Grb10 acts via an Igf independent growth axis Adult mice displayed reduced adipose tissue content mild hypoinsulinemia and improved glucose tolerance Enhanced Insr signalling was observed in cultured adipocytes and muscle

    Original URL path: http://www.imgs.org/Archive/abstracts/2004abstracts/abs/file86.shtml (2016-02-17)
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  • 18th International Mouse Genome Conference (2004)
    1 1 MRC Prion Unit London United Kingdom 2 The Wellcome Trust Centre for Human Genetics Oxford United Kingdom Prion diseases are fatal neurodegenerative disorders of both humans and animals which include scrapie bovine spongiform encephalopathy and Creutzfeldt Jakob disease They are characterised by prolonged incubation periods which in mice can vary from 100 500 days The main genetic determinant of incubation time is the prion gene Prnp where allele a Leu 108 Thr 189 and allele b Phe 108 Val 189 are associated with short and long incubation times respectively Large scale linkage studies have now successfully identified additional modifier loci on at least eight different chromosomes Because the regions of linkage identified in these crosses were broad 10 30cM we are now employing a number of different approaches for fine mapping and candidate gene identification One strategy is to use a heterogeneous stock of mice These are derived from the semi random mating of eight inbred lines of mice A J AKR J BALB cJ C3H HeJ C57BL 6J CBA J DBA 2J and LP J over multiple generations Approximately 1000 mice at generation 37 were inoculated intracerebrally with RML scrapie and incubation times were recorded 400 animals

    Original URL path: http://www.imgs.org/Archive/abstracts/2004abstracts/abs/file87.shtml (2016-02-17)
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  • 18th International Mouse Genome Conference (2004)
    RJ 1 1 Division of Medical Genetics GKT School of Medicine London United Kingdom 2 Division of Human Genetics The Children s Hospital of Philadelphia Philadelphia United States Imprinted genes are expressed in a monoallelic fashion Their pattern of expression is dependant on the parent of origin While one allele is expressed the other allele is epigenetically silenced Mice with uniparental disomies UpDi or uniparental duplications UpDp contain regions of the genome that have originated from just one parent of origin RNA s from these mice can be used to assay genes that are expressed in a parent of origin dependant manner RNA from mice with UpDi of Chromosome 7 has been screened using the Affymetrix GeneChip expression system Gene expression patterns were compared in tissues from embryos with a maternal duplication verses those with a paternal duplication of Chromosome 7 Additional bioinformatic analysis ensured the best candidates for genomic imprinting were selected from the screen Allele specific RT PCR analysis has been used to confirm the imprinting status of seven novel imprinted genes thus far We present here results from screening RNA from mice with UpDi 18 to characterise an imprinted region near the imprinted Impact gene This region

    Original URL path: http://www.imgs.org/Archive/abstracts/2004abstracts/abs/file88.shtml (2016-02-17)
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  • 18th International Mouse Genome Conference (2004)
    United States Linkage studies with the 129 Sv strain which has a low rate 1 5 of spontaneous testicular germ tumors TGCTs reveal exceptional complexity in the genetic control of susceptibility Currently susceptibility genes have not been identified and pathways that lead from primordial germ cells PGCs to stem cells to TGCTs are unknown Various Mendelian traits in mice affect susceptibility only on the 129 Sv genetic background suggesting that these mutations act as modifiers of tumorigenesis We tested pairwise interactions among the five known modifier genes by comparing TGCT frequency in single and double mutant mice to identify combinations that show enhancer or suppressor effects Trp53 Mgf SlJ double mutant males had a tumor frequency that was four fold lower than the rate expected if each modifier acted independently Normally TRP53 arrests cells to allow repair of DNA damage or programmed cell death whereas MGF is essential for survival of PGCs and TGCT stem cells Reduced TGCT susceptibility suggests that interactions between DNA repair apoptosis and MGF KIT signal transduction modulate tumorigenesis Studies are underway to characterize the nature of the interaction between TRP53 and MGF Preliminary results indicate that Trp53 mRNA expression is elevated in the testis of

    Original URL path: http://www.imgs.org/Archive/abstracts/2004abstracts/abs/file89.shtml (2016-02-17)
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  • 18th International Mouse Genome Conference (2004)
    F Dept of Genetics UNC Chapel Hill Chapel Hill United States The DDK syndrome is an early embryonic lethal phenotype that is observed in crosses involving females of the DDK inbred strain and males of other strains This phenotype is the result of an incompatibility between a maternal DDK factor and a non DDK paternal gene both of which have been mapped to the Ovum mutant Om locus on mouse chromosome 11 Previous studies have shown that F 1 hybrid females resulting from crosses involving a non DDK dam and a DDK sire express a semi lethal phenotype when crossed to B6 males It has been suggested that the semi lethal nature of the phenotype in these females is the result of allelic exclusion acting on the Om locus In this study we tested the fertility of several F 1 hybrid females derived from crossing females of classical or wild derived strains with DDK males Although most of the crosses are semi lethal two crosses involving F 1 females from wild derived Mus musculus domesticus strains PERA Ei or PERC Ei are viable Our observations indicate the presence of genetic modifiers of the DDK syndrome that result in dominant rescue

    Original URL path: http://www.imgs.org/Archive/abstracts/2004abstracts/abs/file90.shtml (2016-02-17)
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