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1.
Sci Transl Med ; 16(731): eadd6883, 2024 Jan 24.
Article in English | MEDLINE | ID: mdl-38266108

ABSTRACT

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.


Subject(s)
Down Syndrome , Heart Defects, Congenital , Animals , Humans , Mice , Disease Models, Animal , Down Syndrome/genetics , Genes, Mitochondrial , Heart Defects, Congenital/genetics , Myocytes, Cardiac , Trisomy
2.
Nat Commun ; 14(1): 7844, 2023 Dec 06.
Article in English | MEDLINE | ID: mdl-38057317

ABSTRACT

Migration of T cells is essential for their ability to mount immune responses. Chemokine-induced T cell migration requires WNK1, a kinase that regulates ion influx into the cell. However, it is not known why ion entry is necessary for T cell movement. Here we show that signaling from the chemokine receptor CCR7 leads to activation of WNK1 and its downstream pathway at the leading edge of migrating CD4+ T cells, resulting in ion influx and water entry by osmosis. We propose that WNK1-induced water entry is required to swell the membrane at the leading edge, generating space into which actin filaments can polymerize, thereby facilitating forward movement of the cell. Given the broad expression of WNK1 pathway proteins, our study suggests that ion and water influx are likely to be essential for migration in many cell types, including leukocytes and metastatic tumor cells.


Subject(s)
Actin Cytoskeleton , Actins , Actins/metabolism , Polymerization , Cell Movement/physiology , Actin Cytoskeleton/metabolism , Signal Transduction/physiology
3.
BMC Res Notes ; 16(1): 246, 2023 Sep 30.
Article in English | MEDLINE | ID: mdl-37777793

ABSTRACT

Traditional histological analysis is conducted on thin tissue sections, limiting the data capture from large tissue volumes to 2D profiles, and requiring stereological methods for 3D assessment. Recent advances in microscopical and tissue clearing methods have facilitated 3D reconstructions of tissue structure. However, staining of large tissue blocks remains a challenge, often requiring specialised and expensive equipment to clear and immunolabel tissue. Here, we present the Affordable Brain Slice Optical Clearing (ABSOC) method: a modified iDISCO protocol which enables clearing and immunolabeling of mouse brain slices up to 1 mm thick using inexpensive reagents and equipment, with no intensive expert training required. We illustrate the use of ABSOC in 1 mm C57BL/6J mouse coronal brain slices sectioned through the dorsal hippocampus and immunolabelled with an anti-calretinin antibody. The ABSOC method can be readily used for histological studies of mouse brain in order to move from the use of very thin tissue sections to large volumes of tissue - giving more representative analysis of biological samples, without the need for sampling of small regions only.


Subject(s)
Brain , Microscopy , Mice , Animals , Mice, Inbred C57BL , Microscopy/methods , Imaging, Three-Dimensional/methods , Specimen Handling
4.
Development ; 150(8)2023 04 15.
Article in English | MEDLINE | ID: mdl-37102702

ABSTRACT

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.


Subject(s)
Down Syndrome , Mice , Humans , Animals , Down Syndrome/genetics , Skull , Chromosome Mapping , Phenotype , Disease Models, Animal
5.
Dis Model Mech ; 16(4)2023 04 01.
Article in English | MEDLINE | ID: mdl-36939025

ABSTRACT

Down syndrome (DS) phenotypes result from triplicated genes, but the effects of three copy genes are not well known. A mouse mapping panel genetically dissecting human chromosome 21 (Hsa21) syntenic regions was used to investigate the contributions and interactions of triplicated Hsa21 orthologous genes on mouse chromosome 16 (Mmu16) on skeletal phenotypes. Skeletal structure and mechanical properties were assessed in femurs of male and female Dp9Tyb, Dp2Tyb, Dp3Tyb, Dp4Tyb, Dp5Tyb, Dp6Tyb, Ts1Rhr and Dp1Tyb;Dyrk1a+/+/- mice. Dp1Tyb mice, with the entire Hsa21 homologous region of Mmu16 triplicated, display bone deficits similar to those of humans with DS and served as a baseline for other strains in the panel. Bone phenotypes varied based on triplicated gene content, sex and bone compartment. Three copies of Dyrk1a played a sex-specific, essential role in trabecular deficits and may interact with other genes to influence cortical deficits related to DS. Triplicated genes in Dp9Tyb and Dp2Tyb mice improved some skeletal parameters. As triplicated genes can both improve and worsen bone deficits, it is important to understand the interaction between and molecular mechanisms of skeletal alterations affected by these genes.


Subject(s)
Down Syndrome , Humans , Mice , Male , Female , Animals , Down Syndrome/genetics , Chromosomes, Human, Pair 21 , Disease Models, Animal , Phenotype
6.
iScience ; 26(2): 106073, 2023 Feb 17.
Article in English | MEDLINE | ID: mdl-36818290

ABSTRACT

The Dp(10)2Yey mouse carries a ∼2.3-Mb intra-chromosomal duplication of mouse chromosome 10 (Mmu10) that has homology to human chromosome 21, making it an essential model for aspects of Down syndrome (DS, trisomy 21). In this study, we investigated neuronal dysfunction in the Dp(10)2Yey mouse and report spatial memory impairment and anxiety-like behavior alongside altered neural activity in the medial prefrontal cortex (mPFC) and hippocampus (HPC). Specifically, Dp(10)2Yey mice showed impaired spatial alternation associated with increased sharp-wave ripple activity in mPFC during a period of memory consolidation, and reduced mobility in a novel environment accompanied by reduced theta-gamma phase-amplitude coupling in HPC. Finally, we found alterations in the number of interneuron subtypes in mPFC and HPC that may contribute to the observed phenotypes and highlight potential approaches to ameliorate the effects of human trisomy 21.

7.
J Exp Med ; 220(3)2023 03 06.
Article in English | MEDLINE | ID: mdl-36662229

ABSTRACT

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.


Subject(s)
Antibody Formation , B-Lymphocytes , Mice , Animals , Lymphoid Tissue , Signal Transduction , CD4-Positive T-Lymphocytes , CD40 Antigens/metabolism , WNK Lysine-Deficient Protein Kinase 1/metabolism
8.
Neurobiol Dis ; 188: 106336, 2023 Nov.
Article in English | MEDLINE | ID: mdl-38317803

ABSTRACT

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.


Subject(s)
Down Syndrome , Male , Female , Mice , Animals , Down Syndrome/pathology , Trisomy/genetics , Trisomy/pathology , Glutamine/metabolism , Brain/metabolism , Hippocampus/metabolism , Disease Models, Animal
9.
J Neurosci ; 42(33): 6453-6468, 2022 08 17.
Article in English | MEDLINE | ID: mdl-35835549

ABSTRACT

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the buildup of aggregated amyloid-ß (Aß) and tau proteins in the brain. Aß 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 Aß accumulation (AppNL-F ) to determine how chromosome 21 genes, other than APP, modulate APP/Aß 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 Aß accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene(s) causing this decrease in Aß 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/Aß 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 approach to narrow down the genetic cause of the modulation of pathology, demonstrating that gene(s) on chromosome 21 decrease Aß accumulation in the brain, independently of alterations to full-length APP or C-terminal fragment abundance and that just 38 genes are sufficient to cause this.


Subject(s)
Alzheimer Disease , Down Syndrome , Alzheimer Disease/complications , Alzheimer Disease/genetics , Amyloid beta-Peptides/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Brain/metabolism , Disease Models, Animal , Down Syndrome/complications , Down Syndrome/genetics , Female , Humans , Male , Mice
10.
Nat Commun ; 13(1): 2460, 2022 05 05.
Article in English | MEDLINE | ID: mdl-35513371

ABSTRACT

Infection or vaccination leads to the development of germinal centers (GC) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. Here we follow the migratory pathways of B cells emerging from germinal centers (BEM) and find that many BEM cells migrate into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From the SCS, BEM cells may exit the lymph node to enter distant tissues, while some BEM cells interact with and take up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibits the recycling of BEM cells and results in less efficient adaption to antigenic variation. Our findings thus suggest that the recycling of antigen variant-specific BEM cells and transport of antigen back to GC may support affinity maturation to antigenic drift.


Subject(s)
Antigenic Drift and Shift , Memory B Cells , B-Lymphocytes , Germinal Center , Lymph Nodes
11.
Sci Immunol ; 7(69): eabn3286, 2022 03 11.
Article in English | MEDLINE | ID: mdl-35275754

ABSTRACT

Therapeutic interventions used for cancer treatment provoke thymus damage and limit the recovery of protective immunity. Here, we show that eosinophils are an essential part of an intrathymic type 2 immune network that enables thymus recovery after ablative therapy. Within hours of damage, the thymus undergoes CCR3-dependent colonization by peripheral eosinophils, which reestablishes the epithelial microenvironments that control thymopoiesis. Eosinophil regulation of thymus regeneration occurs via the concerted action of NKT cells that trigger CCL11 production via IL4 receptor signaling in thymic stroma, and ILC2 that represent an intrathymic source of IL5, a cytokine that therapeutically boosts thymus regeneration after damage. Collectively, our findings identify an intrathymic network composed of multiple innate immune cells that restores thymus function during reestablishment of the adaptive immune system.


Subject(s)
Eosinophils , Regeneration , Thymus Gland , Adaptive Immunity , Cytokines , Eosinophils/immunology , Interleukin-5/immunology , Lymphocytes , Thymus Gland/immunology
12.
Mamm Genome ; 33(1): 157-168, 2022 03.
Article in English | MEDLINE | ID: mdl-34719726

ABSTRACT

An organism or cell carrying a number of chromosomes that is not a multiple of the haploid count is in a state of aneuploidy. This condition results in significant changes in the level of expression of genes that are gained or lost from the aneuploid chromosome(s) and most cases in humans are not compatible with life. However, a few aneuploidies can lead to live births, typically associated with deleterious phenotypes. We do not understand why phenotypes arise from aneuploid syndromes in humans. Animal models have the potential to provide great insight, but less than a handful of mouse models of aneuploidy have been made, and no ideal system exists in which to study the effects of aneuploidy per se versus those of raised gene dosage. Here, we give an overview of human aneuploid syndromes, the effects on physiology of having an altered number of chromosomes and we present the currently available mouse models of aneuploidy, focusing on models of trisomy 21 (which causes Down syndrome) because this is the most common, and therefore, the most studied autosomal aneuploidy. Finally, we discuss the potential role of carrying an extra chromosome on aneuploid phenotypes, independent of changes in gene dosage, and methods by which this could be investigated further.


Subject(s)
Chromosome Disorders , Down Syndrome , Aneuploidy , Animals , Chromosome Disorders/genetics , Chromosomes , Disease Models, Animal , Down Syndrome/genetics , Mice , Trisomy
14.
Dis Model Mech ; 14(10)2021 10 01.
Article in English | MEDLINE | ID: mdl-34477842

ABSTRACT

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.


Subject(s)
Down Syndrome/pathology , Amyloid beta-Peptides/metabolism , Anemia/complications , Animals , Bone Development , Disease Models, Animal , Down Syndrome/genetics , Down Syndrome/physiopathology , Erythropoiesis , Evoked Potentials, Auditory, Brain Stem , Gene Expression Regulation , Genes, Duplicate , Hearing , Heart Function Tests , Hippocampus/pathology , Locomotion , Memory/physiology , Mice, Inbred C57BL , Otitis Media/complications , Otitis Media/pathology , Otitis Media/physiopathology , Phenotype , Prediabetic State/complications , Prediabetic State/pathology , Prediabetic State/physiopathology , Respiration , Sleep/physiology , Spleen/pathology , Splenomegaly/complications
15.
Curr Opin Immunol ; 71: 124-131, 2021 08.
Article in English | MEDLINE | ID: mdl-34352467

ABSTRACT

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.


Subject(s)
B-Cell Activating Factor/immunology , B-Cell Activation Factor Receptor/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , B-Lymphocytes/immunology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Signal Transduction/immunology
16.
Nat Commun ; 12(1): 4546, 2021 07 27.
Article in English | MEDLINE | ID: mdl-34315884

ABSTRACT

The NLRP3 inflammasome mediates the production of proinflammatory cytokines and initiates inflammatory cell death. Although NLRP3 is essential for innate immunity, aberrant NLRP3 inflammasome activation contributes to a wide variety of inflammatory diseases. Understanding the pathways that control NLRP3 activation will help develop strategies to treat these diseases. Here we identify WNK1 as a negative regulator of the NLRP3 inflammasome. Macrophages deficient in WNK1 protein or kinase activity have increased NLRP3 activation and pyroptosis compared with control macrophages. Mice with conditional knockout of WNK1 in macrophages have increased IL-1ß production in response to NLRP3 stimulation compared with control mice. Mechanistically, WNK1 tempers NLRP3 activation by balancing intracellular Cl- and K+ concentrations during NLRP3 activation. Collectively, this work shows that the WNK1 pathway has a critical function in suppressing NLRP3 activation and suggests that pharmacological inhibition of this pathway to treat hypertension might have negative clinical implications.


Subject(s)
Chlorides/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pyroptosis , WNK Lysine-Deficient Protein Kinase 1/metabolism , Animals , Caspase 1/metabolism , Female , Imidazoles/pharmacology , Immunity, Innate/drug effects , Interleukin-1beta/metabolism , L-Lactate Dehydrogenase/metabolism , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Male , Mice, Inbred C57BL , Models, Biological , Neutrophils/drug effects , Neutrophils/metabolism , Potassium/metabolism , Protein Serine-Threonine Kinases/metabolism , Pyroptosis/drug effects , Pyrrolidines/pharmacology , Tamoxifen/pharmacology , WNK Lysine-Deficient Protein Kinase 1/antagonists & inhibitors
18.
Nat Commun ; 12(1): 3447, 2021 06 08.
Article in English | MEDLINE | ID: mdl-34103494

ABSTRACT

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.


Subject(s)
Cardiovascular System/embryology , Embryo, Mammalian/pathology , Iron Deficiencies , Animals , Aorta, Thoracic/abnormalities , Biomarkers/metabolism , Cell Differentiation , Coronary Vessels/embryology , Coronary Vessels/pathology , Dietary Supplements , Edema/pathology , Embryo, Mammalian/abnormalities , Embryonic Development , Female , Gene Expression Profiling , Gene-Environment Interaction , Green Fluorescent Proteins/metabolism , Iron/metabolism , Lymphatic Vessels/embryology , Lymphatic Vessels/pathology , Mice, Inbred C57BL , Myocardium/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Penetrance , Phenotype , Pregnancy , Signal Transduction , Stem Cells/pathology , Transgenes , Tretinoin/metabolism
19.
Sci Rep ; 11(1): 5736, 2021 03 11.
Article in English | MEDLINE | ID: mdl-33707583

ABSTRACT

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-ß accumulates in the brain. Amyloid-ß 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/Aß 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-ß 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.


Subject(s)
Amyloid beta-Peptides/genetics , Amyloid beta-Protein Precursor/genetics , Down Syndrome/genetics , Alzheimer Disease/complications , Alzheimer Disease/genetics , Amyloid beta-Peptides/chemistry , Animals , Brain/pathology , Chromosomes, Mammalian/genetics , Disease Models, Animal , Down Syndrome/complications , Mice , Mice, Transgenic , Phenotype , Phosphotransferases/metabolism , Protein Aggregates , Protein-Arginine N-Methyltransferases/metabolism , Segmental Duplications, Genomic , Seizures/complications , Seizures/pathology , Solubility , Survival Analysis , Transgenes
20.
Development ; 148(18)2021 03 12.
Article in English | MEDLINE | ID: mdl-33712441

ABSTRACT

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.


Subject(s)
Anatomic Landmarks/physiopathology , Down Syndrome/physiopathology , Imaging, Three-Dimensional/methods , Animals , Body Weights and Measures/methods , Disease Models, Animal , Female , Male , Mice , Mice, Inbred C57BL , Phenotype , Sex Characteristics , Skull/physiopathology
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