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ABSTRACT: Human trisomy 21 is the most frequent live-born human aneuploidy and causes a constellation of disease phenotypes classified as Down syndrome, which include heart defects, myeloproliferative disorder, cognitive disabilities and Alzheimer-type neurodegeneration. Because these phenotypes are associated with an extra copy of a human chromosome, the genetic analysis of Down syndrome has been a major challenge. To complement human genetic approaches, mouse models have been generated and analyzed based on evolutionary conservation between the human and mouse genomes. These efforts have been greatly facilitated by Cre/loxP-mediated mouse chromosome engineering, which may result in the establishment of minimal critical genomic regions and eventually new dosage-sensitive genes associated with Down syndrome phenotypes. The success in genetic analysis of Down syndrome will further enhance our understanding of this disorder and lead to better strategies in developing effective therapeutic interventions.
Bioengineered bugs 01/2012; 3(1):8-12.
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ABSTRACT: Down syndrome (DS) is mainly caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is a leading genetic cause for developmental cognitive disabilities in humans. The mouse is a premier model organism for DS because the regions on Hsa21 are syntenically conserved with three regions in the mouse genome, which are located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. With the advance of chromosomal manipulation technologies, new mouse mutants have been generated to mimic DS at both the genotypic and phenotypic levels. Further mouse-based molecular genetic studies in the future may lead to the unraveling of the mechanisms underlying DS-associated developmental cognitive disabilities, which would lay the groundwork for developing effective treatments for this phenotypic manifestation. In this review, we will discuss recent progress and future challenges in modeling DS-associated developmental cognitive disability in mice with an emphasis on hippocampus-related phenotypes.
Developmental Neuroscience 08/2011; 33(5):404-13. · 3.63 Impact Factor
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Chunhong Liu,
Masae Morishima,
Tao Yu,
Sei-Ichi Matsui,
Li Zhang,
Dawei Fu,
Annie Pao,
Alberto C Costa,
Katheleen J Gardiner,
John K Cowell,
Norma J Nowak,
Michael S Parmacek,
Ping Liang,
Antonio Baldini, Y Eugene Yu
Human Genetics 04/2011; · 5.07 Impact Factor
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Chunhong Liu,
Masae Morishima,
Tao Yu,
Sei-Ichi Matsui,
Li Zhang,
Dawei Fu,
Annie Pao,
Alberto C Costa,
Katheleen J Gardiner,
John K Cowell,
Norma J Nowak,
Normal J Nowak,
Michael S Parmacek,
Ping Liang,
Antonio Baldini, Y Eugene Yu
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ABSTRACT: Human trisomy 21, the chromosomal basis of Down syndrome (DS), is the most common genetic cause of heart defects. Regions on human chromosome 21 (Hsa21) are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this study, we have analyzed the impact of duplications of each syntenic region on cardiovascular development in mice and have found that only the duplication on Mmu16, i.e., Dp(16)1Yey, is associated with heart defects. Furthermore, we generated two novel mouse models carrying a 5.43-Mb duplication and a reciprocal deletion between Tiam1 and Kcnj6 using chromosome engineering, Dp(16Tiam1-Kcnj6)Yey/+ and Df(16Tiam1-Kcnj6)Yey/+, respectively, within the 22.9-Mb syntenic region on Mmu16. We found that Dp(16Tiam1-Kcnj6)Yey/+, but not Dp(16)1Yey/Df(16Tiam1-Kcnj6)Yey, resulted in heart defects, indicating that triplication of the Tiam1-Knj6 region is necessary and sufficient to cause DS-associated heart defects. Our transcriptional analysis of Dp(16Tiam1-Kcnj6)Yey/+ embryos confirmed elevated expression levels for the genes located in the Tiam-Kcnj6 region. Therefore, we established the smallest critical genomic region for DS-associated heart defects to lay the foundation for identifying the causative gene(s) for this phenotype.
Human Genetics 03/2011; 130(5):623-32. · 5.07 Impact Factor
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ABSTRACT: The mouse has become an important model for understanding human development, physiology and disease because of its genetic and biological similarity to humans. Desired mouse mutants with precise genetic alterations can now be generated through gene targeting in mouse embryonic stem cells. The rate-limiting factor in a gene-targeting experiment is the time needed for cloning to construct targeting vectors. The establishment of the Mutagenic Insertion and Chromosome Engineering Resource has made available targeting vectors for the insertional mutagenesis of a large number of mouse genes as well as for chromosome engineering throughout the mouse genome. This unique resource has enriched the repertoire of the genetic reagents for targeted manipulation of the mouse genome.
Methods in molecular biology (Clifton, N.J.) 01/2011; 693:245-56.
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ABSTRACT: Mutations in the LGI1 gene in humans predispose to the development of autosomal dominant partial epilepsy with auditory features (ADPEAF). Homozygous inactivation of the Lgi1 gene in mice results in an epilepsy phenotype characterized by clonic seizures within 2-3 weeks after birth. Before onset of seizures, the 2-3-week-old null mutant mice show poor locomotor activity and neuromuscular strength. EM analysis of the sciatic nerve demonstrates impaired myelination of axons in the peripheral nervous system. Although heterozygous mutant mice do not show any locomotor phenotypes, they also demonstrate an intermediate level of hypomyelination compared with the wild-type mice. Hypomyelination was also observed in the central nervous system, which, although relatively mild, was still significantly different from that of the wild-type mice. These data suggest a role for LGI1 in the myelination functions of Schwann cells and oligodendrocytes.
Journal of Neuroscience Research 11/2010; 88(15):3328-36. · 2.74 Impact Factor
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Tao Yu,
Chunhong Liu,
Pavel Belichenko,
Steven J Clapcote,
Shaomin Li,
Annie Pao,
Alexander Kleschevnikov,
Allison R Bechard,
Suhail Asrar,
Rongqing Chen,
Ni Fan,
Zhenyu Zhou,
Zhengping Jia,
Chu Chen,
John C Roder,
Bin Liu,
Antonio Baldini,
William C Mobley, Y Eugene Yu
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ABSTRACT: As the genomic basis for Down syndrome (DS), human trisomy 21 is the most common genetic cause of intellectual disability in children and young people. The genomic regions on human chromosome 21 (Hsa21) are syntenic to three regions in the mouse genome, located on mouse chromosome 10 (Mmu10), Mmu16, and Mmu17. Recently, we have developed three new mouse models using chromosome engineering carrying the genotypes of Dp(10)1Yey/+, Dp(16)1Yey/+, or Dp(17)1Yey/+, which harbor a duplication spanning the entire Hsa21 syntenic region on Mmu10, Mmu16, or Mmu17, respectively. In this study, we analyzed the hippocampal long-term potentiation (LTP) and cognitive behaviors of these models. Our results show that, while the genotype of Dp(17)1Yey/+ results in abnormal hippocampal LTP, the genotype of Dp(16)1Yey/+ leads to both abnormal hippocampal LTP and impaired learning/memory. Therefore, these mutant mice can serve as powerful tools for further understanding the mechanism underlying cognitively relevant phenotypes associated with DS, particularly the impacts of different syntenic regions on these phenotypes.
Brain research 10/2010; 1366:162-71. · 2.46 Impact Factor
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Tao Yu,
Steven J Clapcote,
Zhongyou Li,
Chunhong Liu,
Annie Pao,
Allison R Bechard,
Sandra Carattini-Rivera,
Sei-Ichi Matsui,
John C Roder,
Antonio Baldini,
William C Mobley,
Allan Bradley, Y Eugene Yu
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ABSTRACT: Copy-number variation in the human genome can be disease-causing or phenotypically neutral. This type of genetic rearrangement associated with human chromosome 21 (Hsa21) underlies partial Monosomy 21 and Trisomy 21. Mental retardation is a major clinical manifestation of partial Monosomy 21. To model this human chromosomal deletion disorder, we have generated novel mouse mutants carrying heterozygous deletions of the 2.3- and 1.1-Mb segments on mouse chromosome 10 (Mmu10) and Mmu17, respectively, which are orthologous to the regions on human 21q22.3, using Cre/loxP-mediated chromosome engineering. Alterations of the transcriptional levels of genes within the deleted intervals reflect gene-dosage effects in the mutant mice. The analysis of cognitive behaviors shows that the mutant mice carrying the deletion on either Mmu10 or Mmu17 are impaired in learning and memory. Therefore, these mutants represent mouse models for Monosomy 21-associated mental retardation, which can serve as a powerful tool to study the molecular mechanism underlying the clinical phenotype and should facilitate efforts to identify the haploinsufficient causative genes.
Mammalian Genome 06/2010; 21(5-6):258-67. · 2.89 Impact Factor
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ABSTRACT: LGI1 in humans is responsible for a predisposition to autosomal dominant partial epilepsy with auditory features (ADPEAF). However, mechanisms of how LGI1 mutations cause epilepsy remain unclear. We have used a mouse chromosome engineering strategy to create a null mutation for the gene ortholog encoding LGI1. The Lgi1 null mutant mice show no gross overall developmental abnormalities from routine histopathological analysis. After 12-18 days of age, the homozygous mutant mice all exhibit myoclonic seizures accompanied by rapid jumping and running and die shortly thereafter. The heterozygous mutant mice do not develop seizures. Electrophysiological analysis demonstrates an enhanced excitatory synaptic transmission by increasing the release of the excitatory neurotransmitter glutamate, suggesting a basis for the seizure phenotype. This mouse model, therefore, provides novel insights into the mechanism behind ADPEAF and offers a new opportunity to study the mechanism behind the role of LGI1 in susceptibility to myoclonic seizures.
Human Molecular Genetics 05/2010; 19(9):1702-11. · 7.64 Impact Factor
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Tao Yu,
Zhongyou Li,
Zhengping Jia,
Steven J Clapcote,
Chunhong Liu,
Shaomin Li,
Suhail Asrar,
Annie Pao,
Rongqing Chen,
Ni Fan, [......],
Allison R Bechard,
Shoshana Spring,
R Mark Henkelman,
George Stoica,
Sei-Ichi Matsui,
Norma J Nowak,
John C Roder,
Chu Chen,
Allan Bradley, Y Eugene Yu
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ABSTRACT: Down syndrome (DS) is caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is the most common genetic cause for developmental cognitive disability. The regions on Hsa21 are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this report, we describe a new mouse model for DS that carries duplications spanning the entire Hsa21 syntenic regions on all three mouse chromosomes. This mouse mutant exhibits DS-related neurological defects, including impaired cognitive behaviors, reduced hippocampal long-term potentiation and hydrocephalus. These results suggest that when all the mouse orthologs of the Hsa21 genes are triplicated, an abnormal cognitively relevant phenotype is the final outcome of the elevated expressions of these orthologs as well as all the possible functional interactions among themselves and/or with other mouse genes. Because of its desirable genotype and phenotype, this mutant may have the potential to serve as one of the reference models for further understanding the developmental cognitive disability associated with DS and may also be used for developing novel therapeutic interventions for this clinical manifestation of the disorder.
Human Molecular Genetics 05/2010; 19(14):2780-91. · 7.64 Impact Factor
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ABSTRACT: Insulin controls glucose homeostasis and lipid metabolism, and insulin impairment plays a critical role in the pathogenesis of diabetes mellitus. Human skeletal muscle and kidney enriched inositol polyphosphate phosphatase (SKIP) is a member of the phosphatidylinositol 3,4,5-trisphosphate phosphatase family (T. Ijuin et al. J. Biol. Chem. 275:10870-10875, 2000; T. Ijuin and T. Takenawa, Mol. Cell. Biol. 23:1209-1220, 2003). Previous studies showed that SKIP negatively regulates insulin-induced phosphatidylinositol 3-kinase signaling (Ijuin and Takenawa, Mol. Cell. Biol. 23:1209-1220, 2003). We now have generated mice with a targeted mutation of the mouse ortholog of the human SKIP gene, Pps. Adult heterozygous Pps mutant mice show increased insulin sensitivity and reduced diet-induced obesity with increased Akt/protein kinase B (PKB) phosphorylation in skeletal muscle but not in adipose tissue. The insulin-induced uptake of 2-deoxyglucose into the isolated soleus muscle was significantly enhanced in Pps mutant mice. A hyperinsulinemic-euglycemic clamp study also revealed a significant increase in the rate of systemic glucose disposal in Pps mutant mice without any abnormalities in hepatic glucose production. Furthermore, in vitro knockdown studies in L6 myoblast cells revealed that reduction of SKIP expression level increased insulin-stimulated Akt/PKB phosphorylation and 2-deoxyglucose uptake. These results imply that SKIP regulates insulin signaling in skeletal muscle. Thus, SKIP may be a promising pharmacologic target for the treatment of insulin resistance and diabetes.
Molecular and cellular biology 07/2008; 28(17):5184-95. · 6.06 Impact Factor
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ABSTRACT: Down syndrome is caused by a genomic imbalance of human chromosome 21 which is mainly observed as trisomy 21. The regions on human chromosome 21 are syntenically conserved in three regions on mouse chromosomes 10, 16 and 17. Ts65Dn mice, the most widely used model for Down syndrome, are trisomic for approximately 56.5% of the human chromosome 21 syntenic region on mouse chromosome 16. To generate a more complete trisomic mouse model of Down syndrome, we have established a 22.9 Mb duplication spanning the entire human chromosome 21 syntenic region on mouse chromosome 16 in mice using Cre/loxP-mediated long-range chromosome engineering. The presence of the intact duplication in mice was confirmed by fluorescent in situ hybridization and BAC-based array comparative genomic hybridization. The expression levels of the genes within the duplication interval reflect gene-dosage effects in the mutant mice. The cardiovascular and gastrointestinal phenotypes of the mouse model were similar to those of patients with Down syndrome. This new mouse model represents a powerful tool to further understand the molecular and cellular mechanisms of Down syndrome.
Human Molecular Genetics 07/2007; 16(11):1359-66. · 7.64 Impact Factor
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ABSTRACT: Several constitutional chromosomal rearrangements occur on human chromosome 17. Patients who carry constitutional deletions of 17q21.3-q24 exhibit distinct phenotypic features. Within the deletion interval, there is a genomic segment that is bounded by the myeloperoxidase and homeobox B1 genes. This genomic segment is syntenically conserved on mouse chromosome 11 and is bounded by the mouse homologs of the same genes (Mpo and HoxB1). To attain functional information about this syntenic segment in mice, we have generated a 6.9-Mb deletion [Df(11)18], the reciprocal duplication [Dp(11)18] between Mpo and Chad (the chondroadherin gene), and a 1.8-Mb deletion between Chad and HoxB1. Phenotypic analyses of the mutant mouse lines showed that the Dp(11)18/Dp(11)18 genotype was responsible for embryonic or adolescent lethality, whereas the Df(11)18/+ genotype was responsible for heart defects. The cardiovascular phenotype of the Df(11)18/+ fetuses was similar to those of patients who carried the deletions of 17q21.3-q24. Since heart defects were not detectable in Df(11)18/Dp(11)18 mice, the haplo-insufficiency of one or more genes located between Mpo and Chad may be responsible for the abnormal cardiovascular phenotype. Therefore, we have identified a new dosage-sensitive genomic region that may be critical for normal heart development in both mice and humans.
Genetics 06/2006; 173(1):297-307. · 4.01 Impact Factor
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ABSTRACT: Organophosphates induce neurological disorders. One of the enzymes inhibited by these compounds is neuropathy target esterase (NTE). In vitro, inhibition of NTE activity by organophosphates is correlated with inhibition of neurite initiation and reduction of neurite length, supporting the hypothesis that organophosphate-induced neurological disorders are caused by inhibition of NTE activity. However, there is no direct evidence for the involvement of NTE in organophosphate-induced impairment of neurites in vitro. To examine the role of NTE, we have generated NTE-deficient mouse embryonic stem cells. These cells can differentiate into neuron-like cells. Although NTE-deficient cells exhibited a delay in neurite initiation in vitro, both the proportion of neuron-like cells which initiated neurites and the elongation of these neurites occurred at the normal rate. These results demonstrate that NTE activity is not required for neurite initiation or elongation per se, but is essential for the optimal rate of neurite initiation.
Biochemical and Biophysical Research Communications 06/2005; 330(4):1103-9. · 2.48 Impact Factor
