Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down’s syndrome
Tokuyuki Shinohara,Kazuma Tomizuka,Shinichi Miyabara,Shoko Takehara,Yasuhiro Kazuki,Jun Inoue,Motonobu Katoh,Hironobu Nakane,Akihiro Iino,Atsuko Ohguma,Shiro Ikegami,Kaoru Inokuchi,Isao Ishida,Roger H. Reeves,Mitsuo Oshimura +14 more
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TLDR
These chimeric mice mimic a wide variety of phenotypic traits of DS, revealing the utility of mice containing Chr 21 as unique models for DS and for the identification of genes responsible for DS.Abstract:
Trisomy 21 (Ts21) is the most common live-born human aneuploidy; it results in a constellation of features known as Down's syndrome (DS). Ts21 is the most frequent cause of congenital heart defects and the leading genetic cause of mental retardation. To investigate the gene dosage effects of an extra copy of human chromosome 21 (Chr 21) on various phenotypes, we used microcell-mediated chromosome transfer to create embryonic stem (ES) cells containing Chr 21. ES cell lines retaining Chr 21 as an independent chromosome were used to produce chimeric mice with a substantial contribution from Chr 21-containing cells. Fluorescence in situ hybridization and PCR-based DNA analysis revealed that Chr 21 was substationally intact but had sustained a small deletion. The freely segregating Chr 21 was lost during development in some tissues, resulting in a panel of chimeric mice with various mosaicism as regards retention of the Chr 21. These chimeric mice showed a high correlation between retention of Chr 21 in the brain and impairment in learning or emotional behavior by open-field, contextual fear conditioning and forced swim tests. Hypoplastic thymus and cardiac defects, i.e. double outlet right ventricle and riding aorta, were observed in a considerable number of chimeric mouse fetuses with a high contribution of Chr 21. These chimeric mice mimic a wide variety of phenotypic traits of DS, revealing the utility of mice containing Chr 21 as unique models for DS and for the identification of genes responsible for DS.read more
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Journal ArticleDOI
Chromosome 21 and down syndrome: from genomics to pathophysiology.
Stylianos E. Antonarakis,Robert Lyle,Emmanouil T. Dermitzakis,Alexandre Reymond,Samuel Deutsch +4 more
TL;DR: Comparative genomics is beginning to identify the functional components of the chromosome and that in turn will set the stage for the functional characterization of the sequences.
Journal ArticleDOI
In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice.
John F. Cryan,Cedric Mombereau +1 more
TL;DR: It is suggested that it is prudent and most appropriate to use convergent tests that draw on different antidepressant-related endophenotypes, and complimentary physiological analyses in order to provide a program of information concerning whether a given phenotype is functionally relevant to depression-related pathology.
Journal ArticleDOI
An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes
Aideen O'Doherty,Sandra Ruf,Sandra Ruf,Claire Mulligan,Victoria Hildreth,M.L. Errington,Sam F. Cooke,Abdul K. Sesay,Sonie A.C. Modino,Lesley Vanes,Diana Hernandez,Diana Hernandez,Jacqueline M. Linehan,Jacqueline M. Linehan,Paul T. Sharpe,Sebastian Brandner,Tim V. P. Bliss,Deborah J. Henderson,Dean Nizetic,Victor L. J. Tybulewicz,Elizabeth M. C. Fisher +20 more
TL;DR: A trans-species aneuploid mouse line that stably transmits a freely segregating, almost complete human chromosome 21 (Hsa21) is generated, which is a model of trisomy 21, which manifests as Down syndrome in humans and has phenotypic alterations in behavior, synaptic plasticity, cerebellar neuronal number, heart development, and mandible size that relate to human DS.
Journal ArticleDOI
Neurodegenerative disorders associated with diabetes mellitus
TL;DR: Preliminary conclusions suggest that many of the diabetogenic neurodegenerative disorders are related to alterations in oxidative phosphorylation (OXPHOS) and mitochondrial nutrient metabolism, which coincide with aberrant protein precipitation in the majority of affected individuals.
Journal ArticleDOI
Down syndrome and the complexity of genome dosage imbalance
TL;DR: The elucidation of the molecular mechanisms that cause or modify the risk for different Down syndrome phenotypes could lead to the introduction of previously unimaginable therapeutic options.
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Journal ArticleDOI
A mouse model for Down syndrome exhibits learning and behaviour deficits
Roger H. Reeves,N.G. Irving,Timothy H. Moran,Anny Wohn,Cheryl A. Kitt,Sangram S. Sisodia,Cecilia Schmidt,Roderick T. Bronson,Muriel T. Davisson +8 more
TL;DR: In this article, the reproducibility of this phenotype among mice with segmental trisomy 16 (Ts65Dn mice) indicates that dosage imbalance for a gene or genes in this region contributes to this impairment.
Journal ArticleDOI
Down syndrome phenotypes: the consequences of chromosomal imbalance
Julie R. Korenberg,Xiao Ning Chen,R. Schipper,Z. Sun,R. Gonsky,S. Gerwehr,N. Carpenter,C. Daumer,P. Dignan,Christine M. Disteche +9 more
TL;DR: Evidence is provided for a significant contribution of genes outside the D21S55 region to the DS phenotypes, including the facies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics, and mental retardation, which strongly suggests DS is a contiguous gene syndrome and augurs against a single DS chromosomal region responsible for most of the phenotypic features.
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An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes
Aideen O'Doherty,Sandra Ruf,Sandra Ruf,Claire Mulligan,Victoria Hildreth,M.L. Errington,Sam F. Cooke,Abdul K. Sesay,Sonie A.C. Modino,Lesley Vanes,Diana Hernandez,Diana Hernandez,Jacqueline M. Linehan,Jacqueline M. Linehan,Paul T. Sharpe,Sebastian Brandner,Tim V. P. Bliss,Deborah J. Henderson,Dean Nizetic,Victor L. J. Tybulewicz,Elizabeth M. C. Fisher +20 more