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1.
Development ; 150(8)2023 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-37102702

RESUMO

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), occurs in 1 in 800 live births and is the most common human aneuploidy. DS results in multiple phenotypes, including craniofacial dysmorphology, which is characterised by midfacial hypoplasia, brachycephaly and micrognathia. The genetic and developmental causes of this are poorly understood. Using morphometric analysis of the Dp1Tyb mouse model of DS and an associated mouse genetic mapping panel, we demonstrate that four Hsa21-orthologous regions of mouse chromosome 16 contain dosage-sensitive genes that cause the DS craniofacial phenotype, and identify one of these causative genes as Dyrk1a. We show that the earliest and most severe defects in Dp1Tyb skulls are in bones of neural crest (NC) origin, and that mineralisation of the Dp1Tyb skull base synchondroses is aberrant. Furthermore, we show that increased dosage of Dyrk1a results in decreased NC cell proliferation and a decrease in size and cellularity of the NC-derived frontal bone primordia. Thus, DS craniofacial dysmorphology is caused by an increased dosage of Dyrk1a and at least three other genes.


Assuntos
Síndrome de Down , Camundongos , Humanos , Animais , Síndrome de Down/genética , Crânio , Mapeamento Cromossômico , Fenótipo , Modelos Animais de Doenças
2.
Neurobiol Dis ; 188: 106336, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38317803

RESUMO

Down syndrome (DS) is one of the most common birth defects and the most prevalent genetic form of intellectual disability. DS arises from trisomy of chromosome 21, but its molecular and pathological consequences are not fully understood. In this study, we compared Dp1Tyb mice, a DS model, against their wild-type (WT) littermates of both sexes to investigate the impact of DS-related genetic abnormalities on the brain phenotype. We performed in vivo whole brain magnetic resonance imaging (MRI) and hippocampal 1H magnetic resonance spectroscopy (MRS) on the animals at 3 months of age. Subsequently, ex vivo MRI scans and histological analyses were conducted post-mortem. Our findings unveiled the following neuroanatomical and biochemical alterations in the Dp1Tyb brains: a smaller surface area and a rounder shape compared to WT brains, with DS males also presenting smaller global brain volume compared with the counterpart WT. Regional volumetric analysis revealed significant changes in 26 out of 72 examined brain regions, including the medial prefrontal cortex and dorsal hippocampus. These alterations were consistently observed in both in vivo and ex vivo imaging data. Additionally, high-resolution ex vivo imaging enabled us to investigate cerebellar layers and hippocampal sub-regions, revealing selective areas of decrease and remodelling in these structures. An analysis of hippocampal metabolites revealed an elevation in glutamine and the glutamine/glutamate ratio in the Dp1Tyb mice compared to controls, suggesting a possible imbalance in the excitation/inhibition ratio. This was accompanied by the decreased levels of taurine. Histological analysis revealed fewer neurons in the hippocampal CA3 and DG layers, along with an increase in astrocytes and microglia. These findings recapitulate multiple neuroanatomical and biochemical features associated with DS, enriching our understanding of the potential connection between chromosome 21 trisomy and the resultant phenotype.


Assuntos
Síndrome de Down , Masculino , Feminino , Camundongos , Animais , Síndrome de Down/patologia , Trissomia/genética , Trissomia/patologia , Glutamina/metabolismo , Encéfalo/metabolismo , Hipocampo/metabolismo , Modelos Animais de Doenças
3.
PLoS Genet ; 14(5): e1007383, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29746474

RESUMO

Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied-the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in mouse models and, importantly, in humans with DS, that may contribute to locomotor dysfunction.


Assuntos
Síndrome de Down/genética , Atividade Motora/genética , Neurônios Motores/metabolismo , Degeneração Neural/genética , Adulto , Idoso , Animais , Autopsia , Modelos Animais de Doenças , Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Medula Espinal/metabolismo , Medula Espinal/patologia , Quinases Dyrk
4.
Neurobiol Dis ; 105: 235-244, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28624415

RESUMO

Altered concentrations of monoamine neurotransmitters and metabolites have been repeatedly found in people with Down syndrome (DS, trisomy 21). Because of the limited availability of human post-mortem tissue, DS mouse models are of great interest to study these changes and the underlying neurobiological mechanisms. Although previous studies have shown the potential of Ts65Dn mice - the most widely used mouse model of DS - to model noradrenergic changes, a comprehensive monoaminergic characterization in multiple brain regions has not been performed so far. Here, we used RP-HPLC with electrochemical detection to quantify (nor)adrenergic (NA, adrenaline and MHPG), dopaminergic (DA, HVA and DOPAC), and serotonergic compounds (tryptophan, 5-HT and 5-HIAA) in ten regionally dissected brain regions of Ts65Dn mice, as well as in Dp1Tyb mice - a novel DS mouse model. Comparing young adult aneuploid mice (2.5-5.5months) with their euploid WT littermates did not reveal generalized monoaminergic dysregulation, indicating that the genetic overload in these mice barely affected the absolute concentrations at this age. Moreover, we studied the effect of aging in Ts65Dn mice: comparing aged animals (12-13months) with their younger counterparts revealed a large number of significant changes. In general, the (nor)adrenergic system appeared to be reduced, while serotonergic compounds were increased with aging. Dopaminergic alterations were less consistent. These overall patterns appeared to be relatively similar for Ts65Dn and WT mice, though more observed changes were regarded significant for WT mice. Similar human post-mortem studies are necessary to validate the monoaminergic construct validity of the Ts65Dn and Dp1Typ mouse models.


Assuntos
Envelhecimento , Aneuploidia , Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Síndrome de Down/patologia , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Síndrome de Down/genética , Técnicas Eletroquímicas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurotransmissores/metabolismo , Estatísticas não Paramétricas
5.
Front Behav Neurosci ; 18: 1428146, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39050700

RESUMO

Background: Trisomy of human chromosome 21 (Hsa21) results in a constellation of features known as Down syndrome (DS), the most common genetic form of intellectual disability. Hsa21 is orthologous to three regions in the mouse genome on mouse chromosome 16 (Mmu16), Mmu17 and Mmu10. We investigated genotype-phenotype relationships by assessing the contribution of these three regions to memory function and age-dependent cognitive decline, using three mouse models of DS, Dp1Tyb, Dp(17)3Yey, Dp(10)2Yey, that carry an extra copy of the Hsa21-orthologues on Mmu16, Mmu17 and Mmu10, respectively. Hypothesis: Prior research on cognitive function in DS mouse models has largely focused on models with an extra copy of the Mmu16 region and relatively little is known about the effects of increased copy number on Mmu17 and Mmu10 on cognition and how this interacts with the effects of aging. As aging is is a critical contributor to cognitive and psychiatric changes in DS, we hypothesised that ageing would differentially impact memory function in Dp1Tyb, Dp(17)3Yey, and Dp(10)2Yey, models of DS. Methods: Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques. Results: Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques. Conclusion: Our results show that distinct Hsa21-orthologous regions contribute differentially to cognitive dysfunction in DS mouse models and that aging interacts with triplication of Hsa21-orthologous genes on Mmu10.

6.
Sci Transl Med ; 16(731): eadd6883, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38266108

RESUMO

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). DS is a gene dosage disorder that results in multiple phenotypes including congenital heart defects. This clinically important cardiac pathology is the result of a third copy of one or more of the approximately 230 genes on Hsa21, but the identity of the causative dosage-sensitive genes and hence mechanisms underlying this cardiac pathology remain unclear. Here, we show that hearts from human fetuses with DS and embryonic hearts from the Dp1Tyb mouse model of DS show reduced expression of mitochondrial respiration genes and cell proliferation genes. Using systematic genetic mapping, we determined that three copies of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1a) gene, encoding a serine/threonine protein kinase, are associated with congenital heart disease pathology. In embryos from Dp1Tyb mice, reducing Dyrk1a gene copy number from three to two reversed defects in cellular proliferation and mitochondrial respiration in cardiomyocytes and rescued heart septation defects. Increased dosage of DYRK1A protein resulted in impairment of mitochondrial function and congenital heart disease pathology in mice with DS, suggesting that DYRK1A may be a useful therapeutic target for treating this common human condition.


Assuntos
Síndrome de Down , Cardiopatias Congênitas , Animais , Humanos , Camundongos , Modelos Animais de Doenças , Síndrome de Down/genética , Genes Mitocondriais , Cardiopatias Congênitas/genética , Miócitos Cardíacos , Trissomia
7.
Dis Model Mech ; 14(10)2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34477842

RESUMO

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish whether this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes, including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.


Assuntos
Síndrome de Down/patologia , Peptídeos beta-Amiloides/metabolismo , Anemia/complicações , Animais , Desenvolvimento Ósseo , Modelos Animais de Doenças , Síndrome de Down/genética , Síndrome de Down/fisiopatologia , Eritropoese , Potenciais Evocados Auditivos do Tronco Encefálico , Regulação da Expressão Gênica , Genes Duplicados , Audição , Testes de Função Cardíaca , Hipocampo/patologia , Locomoção , Memória/fisiologia , Camundongos Endogâmicos C57BL , Otite Média/complicações , Otite Média/patologia , Otite Média/fisiopatologia , Fenótipo , Estado Pré-Diabético/complicações , Estado Pré-Diabético/patologia , Estado Pré-Diabético/fisiopatologia , Respiração , Sono/fisiologia , Baço/patologia , Esplenomegalia/complicações
8.
J Psychopharmacol ; 32(2): 174-190, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29215943

RESUMO

RATIONALE: The prevalence of Alzheimer's disease is increased in people with Down syndrome. The pathology appears much earlier than in the general population, suggesting a predisposition to develop Alzheimer's disease. Down syndrome results from trisomy of human chromosome 21, leading to overexpression of possible Alzheimer's disease candidate genes, such as amyloid precursor protein gene. To better understand how the Down syndrome context results in increased vulnerability to Alzheimer's disease, we analysed amyloid-ß [25-35] peptide toxicity in the Tc1 mouse model of Down syndrome, in which ~75% of protein coding genes are functionally trisomic but, importantly, not amyloid precursor protein. RESULTS: Intracerebroventricular injection of oligomeric amyloid-ß [25-35] peptide in three-month-old wildtype mice induced learning deficits, oxidative stress, synaptic marker alterations, activation of glycogen synthase kinase-3ß, inhibition of protein kinase B (AKT), and apoptotic pathways as compared to scrambled peptide-treated wildtype mice. Scrambled peptide-treated Tc1 mice presented high levels of toxicity markers as compared to wildtype mice. Amyloid-ß [25-35] peptide injection in Tc1 mice induced significant learning deficits and enhanced glycogen synthase kinase-3ß activity in the cortex and expression of apoptotic markers in the hippocampus and cortex. Interestingly, several markers, including oxidative stress, synaptic markers, glycogen synthase kinase-3ß activity in the hippocampus and AKT activity in the hippocampus and cortex, were unaffected by amyloid-ß [25-35] peptide injection in Tc1 mice. CONCLUSIONS: Tc1 mice present several toxicity markers similar to those observed in amyloid-ß [25-35] peptide-treated wildtype mice, suggesting that developmental modifications in these mice modify their response to amyloid peptide. However, amyloid toxicity led to severe memory deficits in this Down syndrome mouse model.


Assuntos
Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/toxicidade , Síndrome de Down/fisiopatologia , Transtornos da Memória/fisiopatologia , Fragmentos de Peptídeos/toxicidade , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/administração & dosagem , Animais , Biomarcadores/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Síndrome de Down/complicações , Síndrome de Down/genética , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/metabolismo , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Fragmentos de Peptídeos/administração & dosagem , Índice de Gravidade de Doença
9.
Elife ; 52016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26765563

RESUMO

Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is the most common cause of congenital heart defects (CHD), yet the genetic and mechanistic causes of these defects remain unknown. To identify dosage-sensitive genes that cause DS phenotypes, including CHD, we used chromosome engineering to generate a mapping panel of 7 mouse strains with partial trisomies of regions of mouse chromosome 16 orthologous to Hsa21. Using high-resolution episcopic microscopy and three-dimensional modeling we show that these strains accurately model DS CHD. Systematic analysis of the 7 strains identified a minimal critical region sufficient to cause CHD when present in 3 copies, and showed that it contained at least two dosage-sensitive loci. Furthermore, two of these new strains model a specific subtype of atrio-ventricular septal defects with exclusive ventricular shunting and demonstrate that, contrary to current hypotheses, these CHD are not due to failure in formation of the dorsal mesenchymal protrusion.


Down syndrome is a condition caused by having an extra copy of one of the 46 chromosomes found inside human cells. Specifically, instead of two copies, people with Down syndrome are born with three copies of chromosome 21. This results in many different effects, including learning and memory problems, heart defects and Alzheimer's disease. Each of these different effects is caused by having a third copy of one or more of the approximately 230 genes found on chromosome 21. However, it is not known which of these genes cause any of these effects, and how an extra copy of the genes results in such changes. Now, Lana-Elola et al. have investigated which genes on chromosome 21 cause the heart defects seen in Down syndrome, and how those heart defects come about. This involved engineering a new strain of mouse that has an extra copy of 148 mouse genes that are very similar to 148 genes found on chromosome 21 in humans. Like people with Down syndrome, this mouse strain developed heart defects when it was an embryo. Using a series of six further mouse strains, Lana-Elola et al. then narrowed down the potential genes that, when in three copies, are needed to cause the heart defects, to a list of just 39 genes. Further experiments then showed that at least two genes within these 39 genes were required in three copies to cause the heart defects. The next step will be to identify the specific genes that actually cause the heart defects, and then work out how a third copy of these genes causes the developmental problems.


Assuntos
Síndrome de Down/patologia , Cardiopatias Congênitas/genética , Animais , Mapeamento Cromossômico , Modelos Animais de Doenças , Dosagem de Genes , Loci Gênicos , Camundongos
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