Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination.
Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination.
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DOI：
10.1016/j.neuron.2016.01.042
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发表时间：
2016-03-16
期刊：
影响因子：
16.2
通讯作者：
Sestan N
中科院分区：
文献类型：
--
作者：
Olmos-Serrano JL;Kang HJ;Tyler WA;Silbereis JC;Cheng F;Zhu Y;Pletikos M;Jankovic-Rapan L;Cramer NP;Galdzicki Z;Goodliffe J;Peters A;Sethares C;Delalle I;Golden JA;Haydar TF;Sestan N
21三体，或唐氏综合症（DS），是发育迟缓和智力残疾最常见的遗传原因。为了深入了解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的DS和整倍体对照脑进行了多区域转录组分析。我们发现了大量基因表达的全基因组改变，其中许多基因表现出时间和空间特异性，并与不同的生物过程相关。特别是，我们发现了与少突胶质细胞分化和髓鞘形成相关的基因共失调，通过与Ts65Dn三体小鼠的跨物种比较证实了这一点。此外，我们发现Ts65Dn小鼠中存在的低髓鞘形成部分是由于三体对少突胶质细胞分化的细胞自主作用，并导致新皮层动作电位传递较慢。总之，这些结果确定了DS中白质发育和功能的缺陷，并为进一步研究DS的神经发病机制提供了转录框架。
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 provide a transcriptional framework for further investigating DS neuropathogenesis.