Array analysis of epilepsy-associated gangliogliomas reveals expression patterns related to aberrant development of neuronal precursors
Array analysis of epilepsy-associated gangliogliomas reveals expression patterns related to aberrant development of neuronal precursors
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DOI：
10.1093/brain/awn233
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发表时间：
2008-11-01
期刊：
影响因子：
14.5
通讯作者：
Becker, Albert J.
中科院分区：
文献类型：
--
作者：
Fassunke, Jana;Majores, Michael;Becker, Albert J.
神经节细胞胶质瘤是耐药性局灶性癫痫患者中最常见的肿瘤，其特征在于神经胶质和发育不良神经元成分的组织学组合、高度分化的表型和罕见的基因突变。它们的分子基础和与其他低级别脑肿瘤的关系尚未完全了解。由于细胞的复杂性，缺乏合适的对照组织和敏感的表达谱分析方法，对神经节细胞胶质瘤中基因表达改变的系统研究受到阻碍。在这里，我们已经使用离散的显微神经节细胞胶质瘤和相邻的控制脑组织获得的神经外科手术进入肿瘤的相同的患者（n 6）仔细匹配的等效的胶质细胞和神经元元素的寡核苷酸微阵列杂交没有重复扩增足够的量。多变量统计分析确定了丰富的基因表达改变的基因在神经节细胞胶质瘤。通过实时定量RTPCR（qRTPCR）和原位杂交确定，许多差异表达的转录本与细胞内和细胞间信号传导相关，包括蛋白激酶C及其靶点NELL 2在相同的神经节细胞胶质瘤细胞成分中。我们观察到LIM-domain-binding 2（LDB 2）转录本，在胚胎发育过程中对脑发育至关重要，是神经节细胞胶质瘤中最强的减少mRNA之一。随后的qRTPCR在胚胎发育不良性神经上皮肿瘤（n 7）中显示部分表达相似性以及与神经节细胞胶质瘤的显著差异。所展示的基因表达谱将神经节细胞胶质瘤与其他低级别原发性脑肿瘤区分开来。shRNA介导的LDB 2沉默导致培养的发育中的原代海马神经元中显著异常的树突状分支。目前的数据特征的新的分子机制，在神经节细胞胶质瘤，有助于发育不良的神经元和异常的神经元网络的发展。
Gangliogliomas, the most frequent neoplasms in patients with pharmacoresistant focal epilepsies, are characterized by histological combinations of glial and dysplastic neuronal elements, a highly differentiated phenotype and rare gene mutations. Their molecular basis and relationship to other low-grade brain tumours are not completely understood. Systematic investigations of altered gene expression in gangliogliomas have been hampered by their cellular complexity, the lack of suitable control tissue and of sensitive expression profiling approaches. Here, we have used discrete microdissected ganglioglioma and adjacent control brain tissue obtained from the neurosurgical access to the tumour of identical patients (n 6) carefully matched for equivalent glial and neuronal elements in an amount sufficient for oligonucleotide microarray hybridization without repetitive amplification. Multivariate statistical analysis identified a rich profile of genes with altered expression in gangliogliomas. Many differentially expressed transcripts related to intra- and intercellular signalling including protein kinase C and its target NELL2 in identical ganglioglioma cell components as determined by real-time quantitative RTPCR (qRTPCR) and in situ hybridization. We observed the LIM-domain-binding 2 (LDB2) transcript, critical for brain development during embryogenesis, as one of the strongest reduced mRNAs in gangliogliomas. Subsequent qRTPCR in dysembryoplastic neuroepithelial tumours (n 7) revealed partial expression similarities as well as marked differences from gangliogliomas. The demonstrated gene expression profile differentiates gangliogliomas from other low-grade primary brain tumours. shRNA-mediated silencing of LDB2 resulted in substantially aberrant dendritic arborization in cultured developing primary hippocampal neurons. The present data characterize novel molecular mechanisms operating in gangliogliomas that contribute to the development of dysplastic neurons and an aberrant neuronal network.