Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination

Trisomy 21, or Down syndrome (DS), is the most common genetic cause of developmental delay and intellectual disability. To gain insight into the underlying molecular and cellular pathogenesis, we conducted a multi-region transcriptome analysis of DS and euploid control brains spanning from mid-fetal...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2016-03, Vol.89 (6), p.1208-1222
Main Authors: Olmos-Serrano, Jose Luis, Kang, Hyo Jung, Tyler, William A., Silbereis, John C., Cheng, Feng, Zhu, Ying, Pletikos, Mihovil, Jankovic-Rapan, Lucija, Cramer, Nathan P., Galdzicki, Zygmunt, Goodliffe, Joseph, Peters, Alan, Sethares, Claire, Delalle, Ivana, Golden, Jeffrey A., Haydar, Tarik F., Sestan, Nenad
Format: Article
Language:English
Subjects:
Action Potentials - genetics
Adolescent
Adult
Alzheimer's disease
Animals
Brain
Brain - growth & development
Brain - metabolism
Brain - pathology
brain development
Cell Differentiation - genetics
Cell Differentiation - physiology
Child
Child, Preschool
Chromosomes
Chromosomes, Human, Pair 17 - genetics
Disease Models, Animal
Down syndrome
Down Syndrome - genetics
Down Syndrome - pathology
Down Syndrome - physiopathology
Female
Gene expression
Gene Expression Profiling
Gene Expression Regulation, Developmental - genetics
Genomes
genomics
glia
Humans
Infant
Infant, Newborn
Laboratory animals
Male
Mice
Mice, Transgenic
Mosaicism
Myelin Basic Protein - genetics
Myelin Basic Protein - metabolism
Myelin Sheath - metabolism
Myelin Sheath - pathology
Myelin Sheath - ultrastructure
neocortex
Neural Conduction - genetics
neurodevelopmental disorders
Neuropathology
Oligodendroglia - pathology
Postmortem Changes
Principal components analysis
Trisomy - genetics
white matter
White Matter - pathology
White Matter - ultrastructure
Young Adult
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Summary:Trisomy 21, or Down syndrome (DS), is the most common genetic cause of developmental delay and intellectual disability. To gain insight into the underlying molecular and cellular pathogenesis, we conducted a multi-region transcriptome analysis of DS and euploid control brains spanning from mid-fetal development to adulthood. We found genome-wide alterations in the expression of a large number of genes, many of which exhibited temporal and spatial specificity and were associated with distinct biological processes. In particular, we uncovered co-dysregulation of genes associated with oligodendrocyte differentiation and myelination that were validated via cross-species comparison to Ts65Dn trisomy mice. Furthermore, we show that hypomyelination present in Ts65Dn mice is in part due to cell-autonomous effects of trisomy on oligodendrocyte differentiation and results in slower neocortical action potential transmission. Together, these results identify defects in white matter development and function in DS, and they provide a transcriptional framework for further investigating DS neuropathogenesis. •Genome-wide spatiotemporal dysregulation of gene expression is found in DS brains•Transcriptome changes reflect altered oligodendrocyte development and myelination•Oligodendrocyte differentiation and myelination is altered in DS model mice (Ts65Dn)•Speed of action potential propagation is decreased in Ts65Dn neocortical white matter Olmos-Serrano et al. identify defects in oligodendrocyte differentiation and white matter development over the timespan in Down syndrome (DS) brain and in Ts65Dn trisomic mice. Their developmental gene expression study provides a new framework for investigating DS neuropathogenesis.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2016.01.042