Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination

Neuron. 2016 Mar 16;89(6):1208-1222. doi: 10.1016/j.neuron.2016.01.042. Epub 2016 Feb 25.

Abstract

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.

Keywords: brain development; gene expression; genomics; glia; neocortex; neurodevelopmental disorders; white matter.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Action Potentials / genetics
  • Adolescent
  • Adult
  • Animals
  • Brain* / growth & development
  • Brain* / metabolism
  • Brain* / pathology
  • Cell Differentiation / genetics*
  • Cell Differentiation / physiology
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 17 / genetics
  • Disease Models, Animal
  • Down Syndrome / genetics
  • Down Syndrome / pathology*
  • Down Syndrome / physiopathology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mice
  • Mice, Transgenic
  • Mosaicism
  • Myelin Basic Protein / genetics
  • Myelin Basic Protein / metabolism
  • Myelin Sheath / metabolism*
  • Myelin Sheath / pathology
  • Myelin Sheath / ultrastructure
  • Neural Conduction / genetics
  • Oligodendroglia / pathology*
  • Postmortem Changes
  • Trisomy / genetics
  • White Matter / pathology
  • White Matter / ultrastructure
  • Young Adult

Substances

  • Mbp protein, mouse
  • Myelin Basic Protein

Supplementary concepts

  • Chromosome 17 trisomy