222 results found
Redhead Y, Gibbins D, Lana-Elola E, et al., 2023, Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes., Development, Vol: 150
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.
Hayward DA, Vanes L, Wissmann S, et al., 2023, B cell-intrinsic requirement for WNK1 kinase in antibody responses in mice., J Exp Med, Vol: 220
Migration and adhesion play critical roles in B cells, regulating recirculation between lymphoid organs, migration within lymphoid tissue, and interaction with CD4+ T cells. However, there is limited knowledge of how B cells integrate chemokine receptor and integrin signaling with B cell activation to generate efficient humoral responses. Here, we show that the WNK1 kinase, a regulator of migration and adhesion, is essential in B cells for T-dependent and -independent antibody responses. We demonstrate that WNK1 transduces signals from the BCR, CXCR5, and CD40, and using intravital imaging, we show that WNK1 regulates migration of naive and activated B cells, and their interactions with T cells. Unexpectedly, we show that WNK1 is required for BCR- and CD40-induced proliferation, acting through the OXSR1 and STK39 kinases, and for efficient B cell-T cell collaboration in vivo. Thus, WNK1 is critical for humoral immune responses, by regulating B cell migration, adhesion, and T cell-dependent activation.
Mumford P, Tosh J, Anderle S, et al., 2022, Genetic Mapping of APP and Amyloid-β Biology Modulation by Trisomy 21., J Neurosci, Vol: 42, Pages: 6453-6468
Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the buildup of aggregated amyloid-β (Aβ) and tau proteins in the brain. Aβ is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have DS have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of AD in these individuals. Here we use a combination of next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of Aβ accumulation (AppNL-F ) to determine how chromosome 21 genes, other than APP, modulate APP/Aβ in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate Aβ accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene(s) causing this decrease in Aβ accumulation and investigate the role of two lead candidate genes, Dyrk1a and Bace2 Thus, an additional copy of chromosome 21 genes, other than APP, can modulate APP/Aβ in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD in DS, compared with those who have familial AD caused by triplication of APP SIGNIFICANCE STATEMENT Trisomy of chromosome 21 is a commonly occurring genetic risk factor for early-onset Alzheimer's disease (AD), which has been previously attributed to people with Down syndrome having three copies of the amyloid precursor protein (APP) gene, which is encoded on chromosome 21. However, we have shown that an extra copy of other chromosome 21 genes modifies AD-like phenotypes independently of APP copy number (Wiseman et al., 2018; Tosh et al., 2021). Here, we use a mapping a
Redhead Y, Gibbins D, Lana-Elola E, et al., 2022, Craniofacial dysmorphology in Down Syndrome is caused by increased dosage of Dyrk1a and at least three other genes
<jats:title>Abstract</jats:title><jats:p>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, 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 genetic 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 <jats:italic>Dyrk1a</jats:italic>. 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 <jats:italic>Dyrk1a</jats:italic> 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 increased dosage of <jats:italic>Dyrk1a</jats:italic> and at least three other genes.</jats:p><jats:sec><jats:title>Summary statement</jats:title><jats:p>Craniofacial dysmorphology in mouse models of Down syndrome is caused by increased dosage of at least four genes including <jats:italic>Dyrk1a</jats:italic>, resulting in reduced proliferation of neural crest-derived cranial bone progenitors.</jats:p></jats:sec>
Zhang Y, Garcia-Ibanez L, Ulbricht C, et al., 2022, Recycling of memory B cells between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift, NATURE COMMUNICATIONS, Vol: 13
Cosway EJ, White AJ, Parnell SM, et al., 2022, Eosinophils are an essential element of a type 2 immune axis that controls thymus regeneration, SCIENCE IMMUNOLOGY, Vol: 7, ISSN: 2470-9468
Mumford P, Noy S, Tybulewicz VL, et al., 2021, Preclinical modelling in the mouse of altered neuroinflammation in Alzheimer's disease - Down syndrome.
BACKGROUND: People with Down syndrome (DS) develop Alzheimer's disease (AD) pathology, amyloid plaques and neurofibrillary tangles, by age 40 and the majority will develop dementia, due to having three copies of the chromosome 21 (Hsa21) gene APP leading to raised Aβ. How trisomy of the other Hsa21 protein-encoding genes affects AD is unclear (1). People with DS have a perturbed immune system, with elevated pro-inflammatory cytokines and an over-activated interferon response (2,3). Several genes on Hsa21 have been implicated in inflammation differences in DS but how these genes modify neuroinflammation, an important aspect of AD, in AD-DS is unknown. We are investigating how an extra copy of five Hsa21 candidate genes (RUNX1, IFNAR1, IFNAR2, IFNGR2, and IL10RB) modify neuroinflammation. METHOD: Mouse models used had three copies of Hsa21 orthologous genes in the mouse, including our five candidate genes; the Dp2Tyb strain (three copies of ∼33 genes) and Dp1Tyb strain (three copies of ∼148 genes). Techniques used were qPCR, immunohistochemistry, and MSD immunoassay. RESULT: The Dp1Tyb and Dp2Tyb brain has increased expression of Hsa21 candidate genes. The Dp1Tyb model has increased microglia number in the hippocampus, elevated levels of IL-1β, and elevated Oas2, C3, and C1qa expression (n=11 wild-type, n=10 Dp1Tyb). The Dp2Tyb model has elevated levels of interferon-γ in the cortex but few changes to interferon-stimulated genes (n=12 wild-type, n=12 Dp2Tyb). CONCLUSION: The Dp1Tyb and Dp2Tyb models have neuroinflammatory changes that reflect those seen in people with DS, though the phenotypes of the Dp1Tyb are more pronounced. The increased microglial number, IL-1β levels, and neuroinflammatory genes found in the Dp1Tyb were not seen in the Dp2Tyb, suggesting these changes are due to gene(s) which are in three-copies in the Dp1Tyb but not the Dp2Tyb. One such candidate gene is USP25, which was recently found to exacerbate neuroinflammatio
Lana-Elola E, Cater H, Watson-Scales S, et al., 2021, Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes., Dis Model Mech, Vol: 14
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.
Toussaint N, Redhead Y, Vidal-García M, et al., 2021, A landmark-free morphometrics pipeline for high-resolution phenotyping: application to a mouse model of Down syndrome., Development, Vol: 148
Characterising phenotypes often requires quantification of anatomical shape. Quantitative shape comparison (morphometrics) traditionally uses manually located landmarks and is limited by landmark number and operator accuracy. Here, we apply a landmark-free method to characterise the craniofacial skeletal phenotype of the Dp1Tyb mouse model of Down syndrome and a population of the Diversity Outbred (DO) mouse model, comparing it with a landmark-based approach. We identified cranial dysmorphologies in Dp1Tyb mice, especially smaller size and brachycephaly (front-back shortening), homologous to the human phenotype. Shape variation in the DO mice was partly attributable to allometry (size-dependent shape variation) and sexual dimorphism. The landmark-free method performed as well as, or better than, the landmark-based method but was less labour-intensive, required less user training and, uniquely, enabled fine mapping of local differences as planar expansion or shrinkage. Its higher resolution pinpointed reductions in interior mid-snout structures and occipital bones in both the models that were not otherwise apparent. We propose that this landmark-free pipeline could make morphometrics widely accessible beyond its traditional niches in zoology and palaeontology, especially in characterising developmental mutant phenotypes.
Toussaint N, Redhead Y, Vidal-Garcia M, et al., 2021, A landmark-free morphometrics pipeline for high-resolution phenotyping: application to a mouse model of Down syndrome, DEVELOPMENT, Vol: 148, ISSN: 0950-1991
Schweighoffer E, Tybulewicz VL, 2021, BAFF signaling in health and disease., Current Opinion in Immunology, Vol: 71, Pages: 124-131, ISSN: 0952-7915
BAFF is a critical cytokine supporting the survival of mature naïve B cells, acting through the BAFFR receptor. Recent studies show that BAFF and BAFFR are also required for the survival of memory B cells, autoimmune B cells as well as malignant chronic lymphocytic leukaemia (CLL) cells. BAFFR cooperates with other receptors, notably the B cell antigen receptor (BCR), a process which is critical for the expansion of autoimmune and CLL cells. This crosstalk may be mediated by TRAF3 which interacts with BAFFR and with CD79A, a signalling subunit of the BCR and the downstream SYK kinase, inhibiting its activity. BAFF binding to BAFFR leads to degradation of TRAF3 which may relieve inhibition of SYK activity transducing signals to pathways required for B cell survival. BAFFR activates both canonical and non-canonical NF-κB signalling and both pathways play important roles in the survival of B cells and CLL cells.
Mayes-Hopfinger L, Enache A, Xie J, et al., 2021, Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis, NATURE COMMUNICATIONS, Vol: 12, ISSN: 2041-1723
Tosh JL, Rhymes ER, Mumford P, et al., 2021, Publisher Correction: Genetic dissection of down syndrome‑associated alterations in APP/amyloid‑β biology using mouse models., Scientific Reports, Vol: 11, Pages: 1-2, ISSN: 2045-2322
Kalisch-Smith JI, Ved N, Szumska D, et al., 2021, Maternal iron deficiency perturbs embryonic cardiovascular development in mice., Nat Commun, Vol: 12
Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene-environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.
Tosh JL, Rhymes ER, Mumford P, et al., 2021, Genetic dissection of down syndrome-associated alterations in APP/amyloid-β biology using mouse models, Scientific Reports, Vol: 11, ISSN: 2045-2322
Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer's disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or 'dose' of APP is thought to be the cause of this early-onset Alzheimer's disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer's disease in people who have Down syndrome.
Mueller-Winkler J, Mitter R, Rappe JCF, et al., 2021, Critical requirement for BCR, BAFF, and BAFFR in memory B cell survival, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 218, ISSN: 0022-1007
Ma D, Cardoso MJ, Zuluaga MA, et al., 2020, Substantially thinner internal granular layer and reduced molecular layer surface in the cerebellum of the Tc1 mouse model of Down Syndrome - a comprehensive morphometric analysis with active staining contrast-enhanced MRI, NeuroImage, Vol: 223, Pages: 117271-117271, ISSN: 1053-8119
Down Syndrome is a chromosomal disorder that affects the development of cerebellar cortical lobules. Impaired neurogenesis in the cerebellum varies among different types of neuronal cells and neuronal layers. In this study, we developed an imaging analysis framework that utilizes gadolinium-enhanced ex vivo mouse brain MRI. We extracted the middle Purkinje layer of the mouse cerebellar cortex, enabling the estimation of the volume, thickness, and surface area of the entire cerebellar cortex, the internal granular layer, and the molecular layer in the Tc1 mouse model of Down Syndrome. The morphometric analysis of our method revealed that a larger proportion of the cerebellar thinning in this model of Down Syndrome resided in the inner granule cell layer, while a larger proportion of the surface area shrinkage was in the molecular layer.
Kochl R, Vanes L, Sopena ML, et al., 2020, Critical role of WNK1 in MYC-dependent early mouse thymocyte development, ELIFE, Vol: 9, ISSN: 2050-084X
Rayon T, Stamataki D, Perez-Carrasco R, et al., 2020, Species-specific pace of development is associated with differences in protein stability, Science, Vol: 369, Pages: 1-15, ISSN: 0036-8075
INTRODUCTIONWhat determines the pace of embryonic development? Although the molecular and cellular mechanisms of many developmental processes are evolutionarily conserved, the pace at which these operate varies considerably between species. The tempo of embryonic development controls the rate of individual differentiation processes and determines the overall duration of development. Despite its importance, however, the mechanisms that control developmental tempo remain elusive.RATIONALEComparing highly conserved and well-characterized developmental processes in different species permits a search for mechanisms that explain differences in tempo. The specification of neuronal subtype identity in the vertebrate spinal cord is a prominent example, lasting less than a day in zebrafish, 3 to 4 days in mouse, and around 2 weeks in human. The development of the spinal cord involves a well-defined gene regulatory program comprising a series of stereotypic changes in gene expression, regulated by extrinsic signaling as cells differentiate from neural progenitors to postmitotic neurons. The regulatory program and resulting neuronal cell types are highly similar in different vertebrates, despite the difference in tempo between species. We therefore set out to characterize the pace of differentiation of one specific neuronal subtype—motor neurons—in human and mouse and to identify molecular differences that explain differences in pace. To this end, we took advantage of the in vitro recapitulation of in vivo developmental programs using the directed differentiation of human and mouse embryonic stem cells.RESULTSWe found that all stages of the developmental progression from neural progenitor to motor neuron were proportionally prolonged in human compared with mouse, resulting in human motor neuron differentiation taking about 2.5 times longer than mouse. Differences in tempo were not due to differences in the sensitivity of cells to signals, nor could they be attribute
Lana-Elola E, Watson-Scales S, Slender A, et al., 2020, Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel (vol 5, e11614, 2020), ELIFE, Vol: 9, ISSN: 2050-084X
Thomas JR, LaCombe J, Long R, et al., 2020, Interaction of sexual dimorphism and gene dosage imbalance in skeletal deficits associated with Down syndrome, Bone, Vol: 136, ISSN: 1873-2763
All individuals with Down syndrome (DS), which results from trisomy of human chromosome 21 (Ts21), present with skeletal abnormalities typified by craniofacial features, short stature and low bone mineral density (BMD). Differences in skeletal deficits between males and females with DS suggest a sexual dimorphism in how trisomy affects bone. Dp1Tyb mice contain three copies of all of the genes on mouse chromosome 16 that are homologous to human chromosome 21, males and females are fertile, and therefore are an excellent model to test the hypothesis that gene dosage influences the sexual dimorphism of bone abnormalities in DS. Dp1Tyb as compared to control littermate mice at time points associated with bone accrual (6 weeks) and skeletal maturity (16 weeks) showed deficits in BMD and trabecular architecture that occur largely through interactions between sex and genotype and resulted in lower percent bone volume in all female and Dp1Tyb male mice. Cortical bone in Dp1Tyb as compared to control mice exhibited different changes over time influenced by sex × genotype interactions including reduced cortical area in both male and female Dp1Tyb mice. Mechanical testing analyses suggested deficits in whole bone properties such as bone mass and geometry, but improved material properties in female and Dp1Tyb mice. Sexual dimorphisms and the influence of trisomic gene dosage differentially altered cellular properties of male and female Dp1Tyb bone. These data establish sex, gene dosage, skeletal site and age as important factors in skeletal development of DS model mice, paving the way for identification of the causal dosage-sensitive genes. Skeletal differences in developing male and female Dp1Tyb DS model mice replicated differences in less-studied adolescents with DS and established a foundation to understand the etiology of trisomic bone deficits.
Köchl R, Vanes L, Sopena ML, et al., 2020, Critical role of WNK1 in MYC-dependent early thymocyte development
<jats:title>Abstract</jats:title><jats:p>WNK1, a kinase that controls kidney salt homeostasis, also regulates adhesion and migration in CD4<jats:sup>+</jats:sup> T cells. <jats:italic>Wnk1</jats:italic> is highly expressed in thymocytes, and since migration is important for thymocyte maturation, we investigated a role for WNK1 in thymocyte development. We find that WNK1 is required for the transition of double negative (DN) thymocytes through the β-selection checkpoint and subsequent proliferation and differentiation into double positive (DP) thymocytes. Furthermore, we show that WNK1 negatively regulates LFA1-mediated adhesion and positively regulates CXCL12-induced migration in DN thymocytes. Despite this, migration defects of WNK1-deficient thymocytes do not account for the developmental arrest. Instead, we show that in DN thymocytes WNK1 transduces pre-TCR signals via OXSR1 and STK39 kinases and the SLC12A2 ion co-transporter that are required for post-transcriptional upregulation of MYC and subsequent proliferation and differentiation into DP thymocytes. Thus, a pathway regulating ion homeostasis is a critical regulator of thymocyte development.</jats:p>
Chang P, Bush D, Schorge S, et al., 2020, Altered hippocampal-prefrontal neural dynamics in mouse models of down syndrome, Cell Reports, Vol: 30, Pages: 1152-1163.e4, ISSN: 2211-1247
Altered neural dynamics in the medial prefrontal cortex (mPFC) and hippocampus may contribute to cognitive impairments in the complex chromosomal disorder Down syndrome (DS). Here, we demonstrate non-overlapping behavioral differences associated with distinct abnormalities in hippocampal and mPFC electrophysiology during a canonical spatial working memory task in three partially trisomic mouse models of DS (Dp1Tyb, Dp10Yey, and Dp17Yey) that together cover all regions of homology with human chromosome 21 (Hsa21). Dp1Tyb mice show slower decision-making (unrelated to the gene dose of DYRK1A, which has been implicated in DS cognitive dysfunction) and altered theta dynamics (reduced frequency, increased hippocampal-mPFC coherence, and increased modulation of hippocampal high gamma); Dp10Yey mice show impaired alternation performance and reduced theta modulation of hippocampal low gamma; and Dp17Yey mice are not significantly different from the wild type. These results link specific hippocampal and mPFC circuit dysfunctions to cognitive deficits in DS models and, importantly, map them to discrete regions of Hsa21.
Rayon T, Stamataki D, Perez-Carrasco R, et al., 2019, Species-specific developmental timing is associated with global differences in protein stability in mouse and human
<jats:title>ABSTRACT</jats:title><jats:p>What determines the pace of embryonic development? Although many molecular mechanisms controlling developmental processes are evolutionarily conserved, the speed at which these operate can vary substantially between species. For example, the same genetic programme, comprising sequential changes in transcriptional states, governs the differentiation of motor neurons in mouse and human, but the tempo at which it operates differs between species. Using in vitro directed differentiation of embryonic stem cells to motor neurons, we show that the programme runs twice as fast in mouse as in human. We provide evidence that this is neither due to differences in signalling, nor the genomic sequence of genes or their regulatory elements. Instead, we find an approximately two-fold increase in protein stability and cell cycle duration in human cells compared to mouse. This can account for the slower pace of human development, indicating that global differences in key kinetic parameters play a major role in interspecies differences in developmental tempo.</jats:p>
Toussaint N, Redhead Y, Liu W, et al., 2019, Application of high-resolution landmark-free morphometrics to a mouse model of Down Syndrome reveals a tightly localised cranial phenotype
<jats:title>Abstract</jats:title><jats:p>Characterising phenotypes often requires quantification of anatomical shapes. Quantitative shape comparison (morphometrics) traditionally uses anatomical landmarks and is therefore limited by the number of landmarks and operator accuracy when landmarks are located manually. Here we apply a landmark-free method to characterise the craniofacial skeletal phenotype of the Dp1Tyb mouse model of Down syndrome (DS), validating it against a landmark-based approach. We identify cranial dysmorphologies in Dp1Tyb mice, especially smaller size and brachycephaly (front-back shortening) homologous to the human phenotype. The landmark-free phenotyping was less labour-intensive and required less user training than the landmark-based method. It also enabled mapping of local differences as planar expansion or shrinkage. This higher resolution and local mapping pinpointed reductions in interior mid-snout structures and occipital bones in this DS model that were not as apparent using a traditional landmark-based method. This approach could make morphometrics widely-accessible beyond traditional niches in zoology and palaeontology, especially in characterising mutant phenotypes.</jats:p>
Ahlfors H, Anyanwu N, Pakanavicius E, et al., 2019, Gene expression dysregulation domains are not a specific feature of Down syndrome, Nature Communications, Vol: 10, Pages: 1-12, ISSN: 2041-1723
Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), results in a broad range of phenotypes. A recent study reported that DS cells show genome-wide transcriptional changes in which up- or down-regulated genes are clustered in gene expression dysregulation domains (GEDDs). GEDDs were also reported in fibroblasts derived from a DS mouse model duplicated for some Hsa21-orthologous genes, indicating cross-species conservation of this phenomenon. Here we investigate GEDDs using the Dp1Tyb mouse model of DS, which is duplicated for the entire Hsa21-orthologous region of mouse chromosome 16. Our statistical analysis shows that GEDDs are present both in DS cells and in Dp1Tyb mouse fibroblasts and hippocampus. However, we find that GEDDs do not depend on the DS genotype but occur whenever gene expression changes. We conclude that GEDDs are not a specific feature of DS but instead result from the clustering of co-regulated genes, a function of mammalian genome organisation.
Granno S, Nixon-Abell J, Berwick DC, et al., 2019, Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus, Scientific Reports, Vol: 9, ISSN: 2045-2322
Pathological mechanisms underlying Down syndrome (DS)/Trisomy 21, including dysregulation of essential signalling processes remain poorly understood. Combining bioinformatics with RNA and protein analysis, we identified downregulation of the Wnt/β-catenin pathway in the hippocampus of adult DS individuals with Alzheimer's disease and the 'Tc1' DS mouse model. Providing a potential underlying molecular pathway, we demonstrate that the chromosome 21 kinase DYRK1A regulates Wnt signalling via a novel bimodal mechanism. Under basal conditions, DYRK1A is a negative regulator of Wnt/β-catenin. Following pathway activation, however, DYRK1A exerts the opposite effect, increasing signalling activity. In summary, we identified downregulation of hippocampal Wnt/β-catenin signalling in DS, possibly mediated by a dose dependent effect of the chromosome 21-encoded kinase DYRK1A. Overall, we propose that dosage imbalance of the Hsa21 gene DYRK1A affects downstream Wnt target genes. Therefore, modulation of Wnt signalling may open unexplored avenues for DS and Alzheimer's disease treatment.
Hithersay R, Startin CM, Hamburg S, et al., 2018, Association of dementia with mortality among adults with down syndrome older than 35 years, JAMA Neurology, Vol: 76, Pages: 152-160, ISSN: 2168-6149
Importance: This work quantifies the fatal burden of dementia associated with Alzheimer disease in individuals with Down syndrome (DS). Objective: To explore the association of dementia associated with Alzheimer disease with mortality and examine factors associated with dementia in adults with DS. Design, Settings and Participants: Prospective longitudinal study in a community setting in England. Data collection began March 29, 2012. Cases were censored on December 13, 2017. The potential sample consisted of all adults 36 years and older from the London Down Syndrome Consortium cohort with 2 data times and dementia status recorded (N = 300); 6 withdrew from study, 28 were lost to follow-up, and 55 had a single data collection point at time of analysis. The final sample consisted of 211 participants, with 503.92 person-years' follow-up. Exposures: Dementia status, age, sex, APOE genotype, level of intellectual disability, health variables, and living situation. Main Outcomes and Measures: Crude mortality rates, time to death, and time to dementia diagnosis with proportional hazards of predictors. Results: Of the 211 participants, 96 were women (45.5%) and 66 (31.3%) had a clinical dementia diagnosis. Twenty-seven participants (11 female; mean age at death, 56.74 years) died during the study period. Seventy percent had dementia. Crude mortality rates for individuals with dementia (1191.85 deaths per 10 000 person-years; 95% CI, 1168.49-1215.21) were 5 times higher than for those without (232.22 deaths per 10 000 person-years; 95% CI, 227.67-236.77). For those with dementia, APOE ε4 carriers had a 7-fold increased risk of death (hazard ratio [HR], 6.91; 95% CI, 1.756-27.195). For those without dementia, epilepsy with onset after age 36 years was associated with mortality (HR, 9.66; 95% CI, 1.59-58.56). APOE ε4 carriers (HR, 4.91; 95% CI, 2.53-9.56), adults with early-onset epilepsy (HR, 3.61; 95% CI, 1.12-11.60), multiple health comorbidit
Perez-Mazliah D, Gardner PJ, Schweighoffer E, et al., 2018, Plasmodium-specific atypical memory B cells are short-lived activated B cells, eLife, Vol: 7, ISSN: 2050-084X
A subset of atypical memory B cells accumulates in malaria and several infections, autoimmune disorders and aging in both humans and mice. It has been suggested these cells are exhausted long-lived memory B cells, and their accumulation may contribute to poor acquisition of long-lasting immunity to certain chronic infections, such as malaria and HIV. Here, we generated an immunoglobulin heavy chain knock-in mouse with a BCR that recognizes MSP1 of the rodent malaria parasite, Plasmodium chabaudi. In combination with a mosquito-initiated P. chabaudi infection, we show that Plasmodium-specific atypical memory B cells are short-lived and disappear upon natural resolution of chronic infection. These cells show features of activation, proliferation, DNA replication, and plasmablasts. Our data demonstrate that Plasmodium-specific atypical memory B cells are not a subset of long-lived memory B cells, but rather short-lived activated cells, and part of a physiologic ongoing B-cell response.
Wiseman FK, Pulford LJ, Barkus C, et al., 2018, Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP, Brain, Vol: 141, Pages: 2457-2474, ISSN: 1460-2156
Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.
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