title: Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination.
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.
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Olmos-Serrano
authors.affiliation: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Life Science, Chung-Ang University, Seoul, Korea.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Tyler
authors.affiliation: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Silbereis
authors.affiliation: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.|Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Mihovil
authors.initials: M
authors.lastname: Pletikos
authors.affiliation: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Lucija
authors.initials: L
authors.lastname: Jankovic-Rapan
authors.affiliation: Department of Anatomy, Physiology, and Genetics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Cramer
authors.affiliation: Department of Anatomy, Physiology, and Genetics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Zygmunt
authors.initials: Z
authors.lastname: Galdzicki
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Goodliffe
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Peters
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Sethares
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Delalle
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Golden
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Tarik F
authors.initials: TF
authors.lastname: Haydar
authors.affiliation: Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.|Departments of Genetic and Psychiatry, Program in Cellular Neuroscience, Neurodegeneration and Repair, Section of Comparative Medicine and Child Study Center, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Nenad
authors.initials: N
authors.lastname: Sestan
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009030:Mosaicism; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009431:Neural Conduction / Q000235:genetics; D009836:Oligodendroglia / Q000473:pathology*; D011180:Postmortem Changes; D014314:Trisomy / Q000235:genetics; D066127:White Matter / Q000473:pathology / Q000648:ultrastructure; D055815:Young Adult
chemical_list: C499047:Mbp protein, mouse; D004676:Myelin Basic Protein
keywords: brain development; gene expression; genomics; glia; neocortex; neurodevelopmental disorders; white matter