Effects of histone deacetylation inhibition on neuronal differentiation of embryonic mouse neural stem cells
Effects of histone deacetylation inhibition on neuronal differentiation of embryonic mouse neural stem cells
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DOI：
10.1016/j.neuroscience.2006.08.082
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发表时间：
2006-12-28
期刊：
影响因子：
3.3
通讯作者：
Copray, S.
中科院分区：
文献类型：
--
作者：
Balasubramaniyan, V.;Boddeke, E.;Copray, S.
神经干细胞(NSCs)是具有自我更新和分化为神经系统主要细胞类型的多能细胞，即神经元、星形胶质细胞和少突胶质细胞。调控基因转录导致神经干细胞分化和细胞谱系分化的分子机制正在慢慢地被解开。转录调控的一个重要机制是通过组蛋白乙酰化和去乙酰化来调节染色质，允许或阻止转录因子对DNA序列的访问。组蛋白乙酰转移酶和组蛋白脱乙酰酶(HDACs)在神经干细胞分化为成熟功能神经元过程中的确切作用尚不清楚。在这项体外研究中，我们研究了HDAC抑制剂曲古抑素A(TSA)对胚胎小鼠神经干细胞在最低限度、无血清、缺乏任何诱导或生长因子的条件下培养过程中分化模式的影响。我们证明，在这些基本条件下，TSA治疗增加了神经干细胞的神经元分化，减少了星形胶质细胞的分化。最引人注目的是，电生理记录显示，在我们的最低限度的培养系统中，只有经TSA处理的NSC来源的神经元具有正常的电生理膜特性，即可兴奋和放电。此外，TSA处理的神经干细胞来源的神经元的特征是树突延长和树枝状生长。我们的研究表明，HDACs对染色质结构的调节在胚胎神经干细胞神经元分化的转录调控中发挥着重要作用，特别是在功能特性的发育方面。对HDAC活性的调控可能是从NSCs中产生特定神经元群体用于移植的重要工具。(C)2006年IBRO。爱思唯尔有限公司出版。保留所有权利。
Neural stem cells (NSCs) are multipotent cells that have the capacity for self-renewal and for differentiation into the major cell types of the nervous system, i.e. neurons, astrocytes and oligodendrocytes. The molecular mechanisms regulating gene transcription resulting in NSC differentiation and cell lineage specification are slowly being unraveled. An important mechanism in transcriptional regulation is modulation of chromatin by histone acetylation and deacetylation, allowing or blocking the access of transcriptional factors to DNA sequences. The precise involvement of histone acetyltransferases and histone deacetylases (HDACs) in the differentiation of NSCs into mature functional neurons is still to be revealed. In this in vitro study we have investigated the effects of the HDAC inhibitor trichostatin A (TSA) on the differentiation pattern of embryonic mouse NSCs during culture in a minimal, serum-free medium, lacking any induction or growth factor. We demonstrated that under these basic conditions TSA treatment increased neuronal differentiation of the NSCs and decreased astrocyte differentiation. Most strikingly, electrophysiological recordings revealed that in our minimal culture system only TSA-treated NSC-derived neurons developed normal electrophysiological membrane properties characteristic for functional, i.e. excitable and firing, neurons. Furthermore, TSA-treated NSC-derived neurons were characterized by an increased elongation and arborization of the dendrites. Our study shows that chromatin structure modulation by HDACs plays an important role in the transcriptional regulation of the neuronal differentiation of embryonic NSCs particularly as far as the development of functional properties are concerned. Manipulation of HDAC activity may be an important tool to generate specific neuronal populations from NSCs for transplantation purposes. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.