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
Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, Connecticut, USA.
Neuron. 2016 Mar 16;89(6):1208-1222. doi: 10.1016/j.neuron.2016.01.042. Epub 2016 Feb 25.
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.
21三体综合征，即唐氏综合征（DS），是发育迟缓与智力残疾最常见的遗传病因。为深入了解其潜在的分子和细胞发病机制，我们对从胎儿中期发育到成年期的唐氏综合征和整倍体对照大脑进行了多区域转录组分析。我们发现大量基因的表达在全基因组范围内发生改变，其中许多基因表现出时间和空间特异性，并与不同的生物学过程相关。特别地，我们发现与少突胶质细胞分化和髓鞘形成相关的基因存在共同失调，这通过与Ts65Dn三体小鼠的跨物种比较得到验证。此外，我们表明Ts65Dn小鼠中存在的髓鞘形成不足部分是由于三体对少突胶质细胞分化的细胞自主效应，导致新皮质动作电位传导减慢。这些结果共同确定了唐氏综合征中白质发育和功能的缺陷，并为进一步研究唐氏综合征神经发病机制提供了一个转录框架。
