Deficits in human trisomy 21 iPSCs and neurons

Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability, but the precise molecular mechanisms underlying impaired cognition remain unclear. Elucidation of these mechanisms has been hindered by the lack of a model system that contains full trisomy of chromosome 21 (Ts21) in a human genome that enables normal gene regulation. To overcome this limitation, we created Ts21-induced pluripotent stem cells (iPSCs) from two sets of Ts21 human fibroblasts. One of the fibroblast lines had low level mosaicism for Ts21 and yielded Ts21 iPSCs and an isogenic control that is disomic for human chromosome 21 (HSA21). Differentiation of all Ts21 iPSCs yielded similar numbers of neurons expressing markers characteristic of dorsal forebrain neurons that were functionally similar to controls. Expression profiling of Ts21 iPSCs and their neuronal derivatives revealed changes in HSA21 genes consistent with the presence of 50% more genetic material as well as changes in non-HSA21 genes that suggested compensatory responses to oxidative stress. Ts21 neurons displayed reduced synaptic activity, affecting excitatory and inhibitory synapses equally. Thus, Ts21 iPSCs and neurons display unique developmental defects that are consistent with cognitive deficits in individuals with Down syndrome and may enable discovery of the underlying causes of and treatments for this disorder.

[1]  James Briggs,et al.  Integration‐Free Induced Pluripotent Stem Cells Model Genetic and Neural Developmental Features of Down Syndrome Etiology , 2013, Stem cells.

[2]  G. Helguera,et al.  Adaptive downregulation of mitochondrial function in down syndrome. , 2013, Cell metabolism.

[3]  J. Busciglio,et al.  Oxidative Stress and Mitochondrial Dysfunction in Down's Syndrome: Relevance to Aging and Dementia , 2012, Current gerontology and geriatrics research.

[4]  S. Orkin,et al.  A Human Stem Cell Model of Early Alzheimer’s Disease Pathology in Down Syndrome , 2012, Science Translational Medicine.

[5]  D. Butterfield,et al.  Oxidative Stress and Down Syndrome: A Route toward Alzheimer-Like Dementia , 2011, Current gerontology and geriatrics research.

[6]  Yan Liu,et al.  Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network , 2011, Proceedings of the National Academy of Sciences.

[7]  G. Daley,et al.  Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells , 2011, Proceedings of the National Academy of Sciences.

[8]  S. Angers,et al.  Gli proteins in development and disease. , 2011, Annual review of cell and developmental biology.

[9]  Jeanne F. Loring,et al.  A call for standardized naming and reporting of human ESC and iPSC lines. , 2011, Cell stem cell.

[10]  K. Gardiner,et al.  Transcript catalogs of human chromosome 21 and orthologous chimpanzee and mouse regions , 2011, Mammalian Genome.

[11]  Hynek Wichterle,et al.  A functionally characterized test set of human induced pluripotent stem cells , 2011, Nature Biotechnology.

[12]  Michael J. Ziller,et al.  Reference Maps of Human ES and iPS Cell Variation Enable High-Throughput Characterization of Pluripotent Cell Lines , 2011, Cell.

[13]  R. Kirby,et al.  Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004-2006. , 2010, Birth defects research. Part A, Clinical and molecular teratology.

[14]  Stylianos E. Antonarakis,et al.  Down Syndrome: From Understanding the Neurobiology to Therapy , 2010, The Journal of Neuroscience.

[15]  Yoav Mayshar,et al.  Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. , 2010, Cell stem cell.

[16]  O. Yanuka,et al.  Human Embryonic Stem Cells as Models for Aneuploid Chromosomal Syndromes , 2010, Stem cells.

[17]  Richard A Young,et al.  Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. , 2010, Cell stem cell.

[18]  J. Isaac,et al.  Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome , 2010, Nature Neuroscience.

[19]  Shinsuke Yuasa,et al.  Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. , 2010, Cell stem cell.

[20]  Ying Jin,et al.  Pax6 is a human neuroectoderm cell fate determinant. , 2010, Cell stem cell.

[21]  James A Thomson,et al.  Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency , 2010, Proceedings of the National Academy of Sciences.

[22]  M. Johnson,et al.  Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells , 2009, Development.

[23]  C. Svendsen,et al.  A Critical Period in Cortical Interneuron Neurogenesis in Down Syndrome Revealed by Human Neural Progenitor Cells , 2009, Developmental Neuroscience.

[24]  M. Pankratz,et al.  Regulation of Neural Specification from Human Embryonic Stem Cells by BMP and FGF , 2009, Stem cells.

[25]  B. Pakkenberg,et al.  Reduced cell number in the neocortical part of the human fetal brain in Down syndrome. , 2008, Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft.

[26]  Thomas D. Schmittgen,et al.  Analyzing real-time PCR data by the comparative CT method , 2008, Nature Protocols.

[27]  R. Folkerth,et al.  Genomic and functional profiling of human Down syndrome neural progenitors implicates S100B and aquaporin 4 in cell injury. , 2008, Human molecular genetics.

[28]  Shulan Tian,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[29]  T. Haydar,et al.  Defects in Embryonic Neurogenesis and Initial Synapse Formation in the Forebrain of the Ts65Dn Mouse Model of Down Syndrome , 2007, The Journal of Neuroscience.

[30]  C. Epstein,et al.  Synaptic and cognitive abnormalities in mouse models of down syndrome: Exploring genotype‐phenotype relationships , 2007, The Journal of comparative neurology.

[31]  C. Garner,et al.  Over-inhibition: a model for developmental intellectual disability , 2007, Trends in Neurosciences.

[32]  Zhiping P. Pang,et al.  Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines , 2007, Proceedings of the National Academy of Sciences.

[33]  M. Pankratz,et al.  Directed Neural Differentiation of Human Embryonic Stem Cells via an Obligated Primitive Anterior Stage , 2007, Stem cells.

[34]  Z. Janka,et al.  Oxidative stress: A bridge between Down's syndrome and Alzheimer's disease , 2007, Neurobiology of Aging.

[35]  George Perry,et al.  Alzheimer disease, the two-hit hypothesis: an update. , 2007, Biochimica et biophysica acta.

[36]  Su-Chun Zhang.  Neural Subtype Specification from Embryonic Stem Cells , 2006, Brain pathology.

[37]  K. Wisniewski,et al.  Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis. , 2005, American journal of medical genetics. Supplement.

[38]  C J Epstein,et al.  The consequences of chromosome imbalance. , 2005, American journal of medical genetics. Supplement.

[39]  E. Wolvetang,et al.  ets-2 Promotes the Activation of a Mitochondrial Death Pathway in Down's Syndrome Neurons , 2005, The Journal of Neuroscience.

[40]  P. Morrison,et al.  Mosaic Down’s syndrome prevalence in a complete population study , 2004, Archives of Disease in Childhood.

[41]  R. Malenka,et al.  Hippocampal Long-Term Potentiation Suppressed by Increased Inhibition in the Ts65Dn Mouse, a Genetic Model of Down Syndrome , 2004, The Journal of Neuroscience.

[42]  A. Bhattacharyya,et al.  Human neural stem cells: a new tool for studying cortical development in Down's syndrome , 2003, Genes, brain, and behavior.

[43]  Caine W. Wong,et al.  Altered Metabolism of the Amyloid β Precursor Protein Is Associated with Mitochondrial Dysfunction in Down's Syndrome , 2002, Neuron.

[44]  Marius Wernig,et al.  In vitro differentiation of transplantable neural precursors from human embryonic stem cells , 2001, Nature Biotechnology.

[45]  M. Rice,et al.  H(2)O(2) is a novel, endogenous modulator of synaptic dopamine release. , 2001, Journal of neurophysiology.

[46]  S. Antonarakis,et al.  Chromosome 21: from sequence to applications. , 2001, Current opinion in genetics & development.

[47]  J. Richtsmeier,et al.  Too much of a good thing: mechanisms of gene action in Down syndrome. , 2001, Trends in genetics : TIG.

[48]  K. Gardiner,et al.  The sequence of human chromosome 21 and implications for research into Down syndrome , 2000, Genome Biology.

[49]  P. Yarowsky,et al.  Role of Founder Cell Deficit and Delayed Neuronogenesis in Microencephaly of the Trisomy 16 Mouse , 2000, The Journal of Neuroscience.

[50]  Yalin Wang,et al.  Hydrogen Peroxide Inhibits the Vacuolar H+‐ATPase in Brain Synaptic Vesicles at Micromolar Concentrations , 1998, Journal of neurochemistry.

[51]  B. Yankner,et al.  Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro , 1995, Nature.

[52]  B T Hyman,et al.  Development of the Superior Temporal Neocortex Is Anomalous in Trisomy 21 , 1994, Journal of neuropathology and experimental neurology.

[53]  K. Wisniewski,et al.  Brain growth in Down syndrome subjects 15 to 22 weeks of gestational age and birth to 60 months. , 1990, Clinical neuropathology.

[54]  H. Wiśniewski,et al.  Evidence of arrest of neurogenesis and synaptogenesis in brains of patients with Down's syndrome. , 1984, The New England journal of medicine.

[55]  A. Galaburda,et al.  Down's syndrome , 1984, Neurology.

[56]  Sachio Takashima,et al.  Abnormal neuronal development in the visual cortex of the human fetus and infant with down's syndrome. A quantitative and qualitative golgi study , 1981, Brain Research.

[57]  E. Colon.  The Structure of the Cerebral Cortex in Down's Syndrome – A quantitative analysis – , 1972 .

[58]  S. Antonarakis,et al.  Genomic determinants in the phenotypic variability of Down syndrome. , 2012, Progress in brain research.

[59]  Su-Chun Zhang,et al.  Directed differentiation of neural-stem cells and subtype-specific neurons from hESCs. , 2010, Methods in molecular biology.

[60]  B. Thiers.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2008 .

[61]  I. Lott,et al.  Alzheimer's disease in Down syndrome: neurobiology and risk. , 2007, Mental retardation and developmental disabilities research reviews.

[62]  M. Dierssen,et al.  Fetal life in Down syndrome starts with normal neuronal density but impaired dendritic spines and synaptosomal structure. , 2001, Journal of neural transmission. Supplementum.