Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects.
Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects.
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DOI：
10.1371/journal.pgen.1001331
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发表时间：
2011-03
期刊：
影响因子：
4.5
通讯作者：
Wynshaw-Boris A
中科院分区：
文献类型：
--
作者：
Pramparo T;Libiger O;Jain S;Li H;Youn YH;Hirotsune S;Schork NJ;Wynshaw-Boris A
杂合性LIS1突变是人类无脑畸形（一种人类神经元迁移缺陷）最常见的原因，而DCX突变是x连锁无脑畸形最常见的原因。LIS1是包括NDEL1和14-3-3ε在内的蛋白复合物的一部分，调节动力蛋白运动功能和微管动力学，而DCX稳定微管并在神经元迁移和神经发生过程中与LIS1合作。Lis1、Dcx、Ywhae（编码14-3-3ε）和Ndel1基因的靶向突变导致小鼠神经元迁移缺陷，为人类无脑畸形提供模型，并有助于相关神经发育疾病的研究。在这里，我们使用表达微阵列、生物信息学分析和体内/体外实验研究了这四种突变体和野生型小鼠的发育大脑，以确定LIS1神经元迁移复合体不同成员的突变是否会导致相似和/或不同的全局基因表达改变。与突变脑的整体成功发育一致，无监督聚类和共表达分析表明，细胞周期和突触发生基因在WT和突变脑中以时间依赖的方式相似地表达和共同调控。相比之下，Lis1和Ndel1突变体的集中共表达分析揭示了途径之间相关性的实质性差异。差异表达分析显示，在所有突变体中，细胞周期、细胞粘附和细胞骨架组织途径普遍改变，而突触发生、细胞形态和炎症/免疫反应在一个或多个突变体中特异性改变。我们发现了几个位于致病性缺失/重复区域的常见失调基因，它们代表了人类智力迟钝和神经认知障碍的新候选基因。我们的分析表明，在类似疾病的小鼠模型中或在共同途径内的基因表达和途径分析可用于确定相关人类疾病的新候选。神经元迁移是一个确保大脑皮层在发育过程中正常组织的生物学过程。这一过程的失败会导致无脑畸形，这是人类的一种神经元迁移缺陷，也是智力迟钝和顽固性癫痫的重要原因。为了研究这些缺陷，我们通过灭活在神经元迁移中起关键作用的四个基因（Lis1, Dcx， Ywhae和Ndel1）来产生小鼠突变体。这些基因是同一分子复合体（LIS1复合体）的一部分，我们假设它们在神经元迁移和细胞增殖中具有重叠的功能。为了扩大我们对神经元迁移的理解并进一步验证我们的假设，我们使用信息学方法分析了这些突变体中的全局基因表达，并从生物学角度证实了其中一些突变。我们发现一些生物过程在所有突变体中都发生了共同的改变，而另一些只在特定突变体中发生了改变。我们的研究结果为人类神经元迁移缺陷小鼠突变体中调节正常大脑发育的途径和生物学过程提供了新的见解，并提出了一种利用人类遗传疾病小鼠模型的基因表达分析来识别相关疾病（如智力低下和癫痫）的候选基因的基因组方法。
Heterozygous LIS1 mutations are the most common cause of human lissencephaly, a human neuronal migration defect, and DCX mutations are the most common cause of X-linked lissencephaly. LIS1 is part of a protein complex including NDEL1 and 14-3-3ε that regulates dynein motor function and microtubule dynamics, while DCX stabilizes microtubules and cooperates with LIS1 during neuronal migration and neurogenesis. Targeted gene mutations of Lis1, Dcx, Ywhae (coding for 14-3-3ε), and Ndel1 lead to neuronal migration defects in mouse and provide models of human lissencephaly, as well as aid the study of related neuro-developmental diseases. Here we investigated the developing brain of these four mutants and wild-type mice using expression microarrays, bioinformatic analyses, and in vivo/in vitro experiments to address whether mutations in different members of the LIS1 neuronal migration complex lead to similar and/or distinct global gene expression alterations. Consistent with the overall successful development of the mutant brains, unsupervised clustering and co-expression analysis suggested that cell cycle and synaptogenesis genes are similarly expressed and co-regulated in WT and mutant brains in a time-dependent fashion. By contrast, focused co-expression analysis in the Lis1 and Ndel1 mutants uncovered substantial differences in the correlation among pathways. Differential expression analysis revealed that cell cycle, cell adhesion, and cytoskeleton organization pathways are commonly altered in all mutants, while synaptogenesis, cell morphology, and inflammation/immune response are specifically altered in one or more mutants. We found several commonly dysregulated genes located within pathogenic deletion/duplication regions, which represent novel candidates of human mental retardation and neurocognitive disabilities. Our analysis suggests that gene expression and pathway analysis in mouse models of a similar disorder or within a common pathway can be used to define novel candidates for related human diseases. Neuronal migration is a biological process that ensures proper organization of the cerebral cortex during development. Failure of this process leads to lissencephaly, a neuronal migration defect in humans and an important cause of mental retardation and intractable epilepsy. To study these defects, we generated mouse mutants by inactivating four genes (Lis1, Dcx, Ywhae, and Ndel1) that play a crucial role in neuronal migration. These genes are part of the same molecular complex (LIS1 complex) that we hypothesize have overlapping functions in neuronal migration and cell proliferation. To broaden our understanding of neuronal migration and to further test our hypothesis, we analyzed global gene expression in these mutants using informatic approaches, confirming some of them biologically. We found that several biological processes were commonly altered in all mutants, while others were altered only in specific mutants. Our results provide new insights into the pathways and biological processes that regulate normal brain development and that are altered in mouse mutants of human neuronal migration defects, and they suggest a genomic approach to use gene expression analysis of mouse models of human genetic disease to identify candidate genes for related disorders, such as mental retardation and epilepsy.