Mouse trisomy 16 as an animal model of human trisomy 21 (Down syndrome): production of viable trisomy 16 diploid mouse chimeras.
ABSTRACT We have previously proposed that mice trisomic for chromosome 16 will provide an animal model of human trisomy 21 (Down syndrome). However, the value of this model is limited to some extent because trisomy 16 mouse fetuses do not survive as live-born animals. Therefore, in an effort to produce viable mice with cells trisomic for chromosome 16, we have used an aggregation technique to generate trisomy 16 diploid (Ts 16 2n) chimeras. A total of 79 chimeric mice were produced, 11 of which were Ts 16 2n chimeras. Seven of these Ts 16 2n mice were analyzed as fetuses, just prior to birth, and 4 were analyzed as live-born animals. Unlike nonchimeric Ts 16 mouse fetuses which die shortly before birth with edema, congenital heart disease, and thymic and splenic hypoplasia, all but 1 of the Ts 16 2n animals were viable and phenotypically normal. The oldest of the live-born Ts 16 2n chimeras was 12 months old at the time of necropsy. Ts 16 cells, identified by coat color, enzyme marker, and/or karyotype analyses, comprised 50-60% of the brain, heart, lung, liver, and kidney in the 7 Ts 16 2n chimeric fetuses and 30-40% of these organs in the 4 live-born Ts 16 2n animals. Ts 16 cells comprised an average of 40% of the thymus and 80% of the spleen in the Ts 16 2n chimeras analyzed as fetuses, with no evidence of thymic or splenic hypoplasia. However, we observed a marked deficiency to Ts 16 cells in the blood, spleen, thymus, and bone marrow of live-born Ts 16 2n chimeras as compared to 2n 2n controls. These results demonstrate that although the Ts 16 2n chimeras were, with one exception, viable and phenotypically normal, each animal contained a significant proportion of trisomic cells in a variety of tissues, including the brain. Furthermore, our results suggest that although the abnormal development of Ts 16 thymus and spleen cells observed in Ts 16 fetuses is largely corrected in Ts 16 2n fetuses, Ts 16 erythroid and lymphoid cells have a severe proliferative disadvantage as compared to diploid cells in older live-born Ts 16 2n chimeras. Ts 16 2n chimeric mice will provide a valuable tool for studying the functional consequences of aneuploidy and may provide insight into the mechanisms by which trisomy 21 leads to developmental abnormalities in man.
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ABSTRACT: Down syndrome (DS), affecting 1/700 live births, is the major genetic cause of mental retardation (MR), a cognitive disorder with hard impact on public health. DS brain is characterized by a reduced cerebellar volume and number of granular cells, defective cortical lamination and reduced cortical neurons, malformed dendritic trees and spines, and abnormal synapses. These neurological alterations, also found in trisomic mouse models, result from gene-dosage effects of Human Chromosome 21 (HC21) on the expression of critical developmental genes. HC21 sequencing, mouse ortholog gene identification and DS mouse model generation lead to determine HC21 gene functions and the effects of protein-dosage alterations in neurodevelopmental and metabolic pathways in DS individuals. Trisomic brain transcriptome of DS patients and trisomic mouse models identified some molecular changes determined by gene-overdosage and associated dysregulation of some disomic gene expression in DS brains. These transcriptional variations cause developmental alterations in neural patterning and signal transduction pathways that may lead to defective neuronal circuits responsible for the pathogenesis of MR in DS. Recently, the first altered molecular pathway responsible of some DS phenotypes, including neurological and cognitive disorders has been identified. In this pathway, two critical HC21 genes (DYRK1A and DSCR1) act synergistically to control the phosphorylation levels of NFATc and NFATc-regulated gene expression. Interestingly, the NFATc mice show neurological dysfunctions similar to those seen in DS patients and trisomic mouse models. Treatment of DS mouse model Ts65Dn with GABA(A) antagonists allowed post-drug rescue of cognitive defects, indicating a hopeful direction in clinical therapies for MR in children with DS.European Journal of Paediatric Neurology 06/2008; 12(3):168-82. · 1.98 Impact Factor
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ABSTRACT: ABSTRACT Mouse trisomy 16, which was induced by mating males of Rb(16.17)7 Bnr/Rb(9.16)9Rma with three different strains of female, C57BL/6, C57BL/10 and C3H/He, was examined in fetuses and newborns in terms of incidence of occurrence, malformations and sex ratio. The incidence of trisomies tended to be higher in C3H/He than in C57BL/6 and C57BL/10. Trisomies could not survive beyond term in C57BL/6, which was most thoroughly examined in the three strains. Trisomy-associated generalized edema, beginning to appear on day 14 of pregnancy on fetus's back, reached the maximum on day 16 in all strains. On cardiovascular anomalies, persistent common atrioventricular canal was observed in virtually all trisomies from C57BL/10 and C57BL/6, while in about 80% from C3H/He. In conotruncal region, all trisomies from former two crossing exhibited double outlet right ventricle or persistent truncus arteriosus. In addition to these anomalies, riding aorta was found in C3H/He. Hydroureter and hydronephrosis developed from day 17 of pregnancy in trisomies other than those in C57BL/10. The histological study of gonads revealed that trisomy 16 tended to be predominant in males of each crossing. The anomalies encountered in mouse trisomy 16, such as edema, persistent common atrioventricular canal, and hydroureter and hydronephrosis appeared to be in common with human trisomy 21 embryos and fetuses. The tendency of predominance of mouse trisomies in males may provide further homology to human trisomy 21. It is supposed that genetic background by different female strains may affect phenotypic expression of malformations. The extremely high incidence of cardiovascular anomalies is regarded as suitable material for elucidation of pathogenesis.Congenital Anomalies 05/2008; 24(4):283 - 292.
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ABSTRACT: Down syndrome (DS), caused by a genomic imbalance of human chromosome 21 (HSA21), is mainly observed as trisomy 21 and is the major genetic cause of mental retardation (MR). MR and associated neurological and behavioural alterations result from dysregulation in critical HSA21 genes and associated molecular pathways. Gene expression, transcriptome, proteome and functional genomics studies, in human, trisomic and transgenic mouse models have shown similar genotype/phenotype correlation and parallel outcomes suggesting that the same evolutionarily conserved genetic programmes are perturbed by gene-dosage effects. The expression variations caused by this gene-dosage imbalance may firstly induce brain functional variations at cellular level, as primary phenotypes, and finally induce neuromorphological alterations and cognitive deficits as secondary phenotypes. The identification of trisomic genes overexpressed in the brain and their function, their developmental regulated expression and their downstream effects, their interaction with other proteins, and their involvement in regulatory and metabolic pathways is giving a clearer view of the origin of the MR in DS. This led to the identification of potential targets in the altered molecular pathways involved in MR pathogenesis, such as calcineurin, NFATs and MAPK pathways, that may be potentially corrected, in the perspective of new therapeutic approaches. Treatment of DS mouse models with NMDA receptor or GABAA antagonists allowed post-drug rescue of cognitive deficits. Besides these new pharmacotherapies, the regulation of gene expression by microRNAs or small interfering RNAs provide exciting possibilities for exogenous correction of the aberrant gene expression in DS and provide potential directions for clinical therapeutics of MR. Herein, we highlight the genetic networks and molecular mechanisms implicated in the pathogenesis of MR in DS and, thereafter, we outline some of the therapeutic strategies for the treatment of this as yet incurable cognitive disorder with a considerable impact on public health. KeywordsTrisomy 21-Mental retardation-Learning and memory-Down syndrome critical region-Genotype-phenotype correlation-Mouse models-Gene-dosage imbalance-Transcriptome-Proteome-MicroRNAs-Gene expression variation-Molecular mechanism model-NFATs/calcineurin pathways-NMDA receptor antagonist-GABAA antagonists-Pharmacotherapy12/2010: pages 21-86;