Balasubramaniyan V, Boddeke E, Bakels R, Küst B, Kooistra S, Veneman A, Copray S
Department of Medical Physiology, University Medical Center Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Neuroscience. 2006 Dec 28;143(4):939-51. doi: 10.1016/j.neuroscience.2006.08.082. Epub 2006 Nov 3.
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.
神经干细胞（NSCs）是多能细胞，具有自我更新能力，并能分化为神经系统的主要细胞类型，即神经元、星形胶质细胞和少突胶质细胞。调节基因转录从而导致神经干细胞分化和细胞谱系特化的分子机制正逐渐被揭示。转录调控中的一个重要机制是通过组蛋白乙酰化和去乙酰化对染色质进行调节，从而允许或阻止转录因子与DNA序列结合。组蛋白乙酰转移酶和组蛋白去乙酰化酶（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仍有待揭示。在这项体外研究中，我们研究了HDAC抑制剂曲古抑菌素A（TSA）对胚胎小鼠神经干细胞在缺乏任何诱导因子或生长因子的基本无血清培养基中培养时分化模式的影响。我们证明，在这些基本条件下，TSA处理可增加神经干细胞的神经元分化并减少星形胶质细胞分化。最引人注目的是，电生理记录显示，在我们的基本培养系统中，只有经TSA处理的神经干细胞来源的神经元才具有功能性（即可兴奋和放电）神经元特有的正常电生理膜特性。此外，经TSA处理的神经干细胞来源的神经元的特征是树突的伸长和分支增加。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起着重要作用，特别是在功能特性的发育方面。操纵HDAC活性可能是从神经干细胞生成特定神经元群体用于移植目的的重要工具。
