The coordination of progenitor self-renewal, neuronal production, and migration is essential to the normal development and evolution of the cerebral cortex. Numerous studies have shown that the Notch, Wnt/beta-catenin, and Neurogenin pathways contribute separately to progenitor expansion, neurogenesis, and neuronal migration, but it is unknown how these signals are coordinated. In vitro studies suggested that the mastermind-like 1 (MAML1) gene, homologue of the Drosophila mastermind, plays a role in coordinating the aforementioned signaling pathways, yet its role during cortical development remains largely unknown. Here we show that ectopic expression of dominant-negative MAML (dnMAML) causes exuberant neuronal production in the mouse cortex without disrupting neuronal migration. Comparing the transcriptional consequences of dnMAML and Neurog2 ectopic expression revealed a complex genetic network controlling the balance of progenitor expansion versus neuronal production. Manipulation of MAML and Neurog2 in cultured human cerebral stem cells exposed interactions with the same set of signaling pathways. Thus, our data suggest that evolutionary changes that affect the timing, tempo, and density of successive neuronal layers of the small lissencephalic rodent and large convoluted primate cerebral cortex depend on similar molecular mechanisms that act from the earliest developmental stages.

中文翻译：

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果蝇主要成分蛋白的同源物在小鼠和人类大脑皮层中神经元产生的协调。

祖细胞自我更新，神经元产生和迁移的协调对于大脑皮质的正常发育和进化至关重要。大量研究表明，Notch，Wnt /β-catenin和Neurogenin途径分别促进祖细胞的扩增，神经发生和神经元迁移，但是尚不清楚这些信号如何协调。体外研究表明，果蝇原虫的同源物Mastermind-like 1（MAML1）基因在协调上述信号传导途径中起着一定的作用，但在皮质发育过程中的作用仍然未知。在这里，我们显示显性阴性MAML（dnMAML）的异位表达在小鼠皮质中引起旺盛的神经元产生，而不会破坏神经元迁移。比较dnMAML和Neurog2异位表达的转录结果，发现一个复杂的遗传网络控制着祖细胞扩增与神经元产生的平衡。在培养的人脑干细胞中对MAML和Neurog2的操纵暴露了与同一组信号通路的相互作用。因此，我们的数据表明，影响小中脑啮齿动物和大盘旋灵长类大脑皮层的连续神经元层的时间，速度和密度的进化变化取决于从最早的发育阶段起起作用的相似分子机制。在培养的人脑干细胞中对MAML和Neurog2的操纵暴露了与同一组信号通路的相互作用。因此，我们的数据表明，影响小中脑性啮齿动物和大盘旋灵长类大脑皮层的连续神经元层的时序，速度和密度的进化变化取决于从最早的发育阶段起起作用的相似分子机制。在培养的人脑干细胞中对MAML和Neurog2的操纵暴露了与同一组信号通路的相互作用。因此，我们的数据表明，影响小中脑性啮齿动物和大盘旋灵长类大脑皮层的连续神经元层的时序，速度和密度的进化变化取决于从最早的发育阶段起起作用的相似分子机制。