Dab2ip regulates neuronal migration and neurite outgrowth in the developing neocortex.
Dab2ip regulates neuronal migration and neurite outgrowth in the developing neocortex.
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DOI：
10.1371/journal.pone.0046592
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
D'Arcangelo G
中科院分区：
文献类型：
--
作者：
Lee GH;Kim SH;Homayouni R;D'Arcangelo G
Dab 2 ip（DOC-2/DAB 2相互作用蛋白）是Ras GTP酶激活蛋白（GAP）家族的成员，其先前已显示在若干系统中作为肿瘤抑制剂起作用。Dab 2 ip也在大脑中高度表达，它与Dab 1相互作用，Dab 1是Reelin途径的关键介质，控制大脑发育和功能的几个方面。我们发现Dab 2 ip在发育中的大脑皮层中高度表达，但Reelin信号通路的突变并不影响其表达。为了确定Dab 2 ip是否在脑发育中起作用，我们使用子宫内电穿孔在胚胎小鼠新皮质的神经元祖细胞中敲低或过表达它。dab 2 ip下调严重破坏神经元迁移，优先影响晚出生的主要皮层神经元。dab 2 ip过表达也导致迁移缺陷。体内结构-功能实验进一步表明Dab 2 ip的PH和GRD结构域对神经元迁移都很重要。转染神经元的详细分析表明，Dab 2 ip下调或上调破坏了中间区从多极到双极神经元形态的转变。Dab 2 ip在离体神经元中的敲低表明，该蛋白质对于适当的神经突发育和几种主要的神经元微管相关蛋白（MAP）的表达是必需的，这对神经突生长和稳定是重要的。因此，我们的研究首次确定了Dab 2 ip在哺乳动物皮层发育中的关键作用，并开始揭示这种功能的分子机制。
Dab2ip (DOC-2/DAB2 interacting protein) is a member of the Ras GTPase-activating protein (GAP) family that has been previously shown to function as a tumor suppressor in several systems. Dab2ip is also highly expressed in the brain where it interacts with Dab1, a key mediator of the Reelin pathway that controls several aspects of brain development and function. We found that Dab2ip is highly expressed in the developing cerebral cortex, but that mutations in the Reelin signaling pathway do not affect its expression. To determine whether Dab2ip plays a role in brain development, we knocked down or over expressed it in neuronal progenitor cells of the embryonic mouse neocortex using in utero electroporation. Dab2ip down-regulation severely disrupts neuronal migration, affecting preferentially late-born principal cortical neurons. Dab2ip overexpression also leads to migration defects. Structure-function experiments in vivo further show that both PH and GRD domains of Dab2ip are important for neuronal migration. A detailed analysis of transfected neurons reveals that Dab2ip down- or up-regulation disrupts the transition from a multipolar to a bipolar neuronal morphology in the intermediate zone. Knock down of Dab2ip in neurons ex-vivo indicates that this protein is necessary for proper neurite development and for the expression of several major neuronal microtubule associated proteins (MAPs), which are important for neurite growth and stabilization. Thus, our study identifies, for the first time, a critical role for Dab2ip in mammalian cortical development and begins to reveal molecular mechanisms that underlie this function.
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