Arx Is a Direct Target of Dlx2 and Thereby Contributes to the Tangential Migration of GABAergic Interneurons
Arx Is a Direct Target of Dlx2 and Thereby Contributes to the Tangential Migration of GABAergic Interneurons
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DOI：
10.1523/jneurosci.1283-08.2008
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发表时间：
2008-10-15
影响因子：
5.3
通讯作者：
Broccoli, Vania
中科院分区：
文献类型：
--
作者：
Colasante, Gaia;Collombat, Patrick;Broccoli, Vania
Arx转录因子在发育中的腹侧端脑及其衍生物的子集中表达。人类ARX直系同源物的突变导致神经系统疾病，包括癫痫、无脑畸形和智力迟钝。我们已经分离出小鼠Arx内源性增强子模块，控制其紧密区室化的前脑表达。有趣的是，它们分散在其编码区的下游，并部分包含在下游PolA1基因的内含子内。这些增强子是在整个脊椎动物门中高度保守的超保守非编码序列。Arx GABA能增强子元件的功能表征揭示其严格依赖于Dlx转录因子的活性。Dlx过表达诱导内源性Arx及其分离的增强子的异位表达，而Dlx表达的丧失导致Arx表达减少，表明Arx是Dlx功能的关键介质。为了进一步阐明所涉及的机制，在突变体Arx或Dlx组织中进行了功能获得性研究的组合。该分析提供的证据表明，虽然Arx是Dlx依赖性促进中间神经元迁移所必需的，但它不是Dlx因子介导的GABA能细胞命运定型所必需的。虽然Arx具有独立于Dlx通路的额外功能，但我们已经建立了控制端脑GABA能神经元发育关键步骤的直接遗传关系。这些发现有助于阐明可能构成各种人类神经发育障碍病因学基础的遗传层次结构。
The Arx transcription factor is expressed in the developing ventral telencephalon and subsets of its derivatives. Mutation of human ARX ortholog causes neurological disorders including epilepsy, lissencephaly, and mental retardation. We have isolated the mouse Arx endogenous enhancer modules that control its tightly compartmentalized forebrain expression. Interestingly, they are scattered downstream of its coding region and partially included within the introns of the downstream PolA1 gene. These enhancers are ultraconserved noncoding sequences that are highly conserved throughout the vertebrate phylum. Functional characterization of the Arx GABAergic enhancer element revealed its strict dependence on the activity of Dlx transcription factors. Dlx overexpression induces ectopic expression of endogenous Arx and its isolated enhancer, whereas loss of Dlx expression results in reduced Arx expression, suggesting that Arx is a key mediator of Dlx function. To further elucidate the mechanisms involved, a combination of gain-of-function studies in mutant Arx or Dlx tissues was pursued. This analysis provided evidence that, although Arx is necessary for the Dlx-dependent promotion of interneuron migration, it is not required for the GABAergic cell fate commitment mediated by Dlx factors. Although Arx has additional functions independent of the Dlx pathway, we have established a direct genetic relationship that controls critical steps in the development of telencephalic GABAergic neurons. These findings contribute elucidating the genetic hierarchy that likely underlies the etiology of a variety of human neurodevelopmental disorders.