Dab2IP Regulates Neuronal Positioning, Rap1 Activity and Integrin Signaling in the Developing Cortex.
Dab2IP Regulates Neuronal Positioning, Rap1 Activity and Integrin Signaling in the Developing Cortex.
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DOI：
10.1159/000369092
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发表时间：
2015
影响因子：
2.9
通讯作者：
Homayouni R
中科院分区：
文献类型：
--
作者：
Qiao S;Homayouni R
Dab2IP （DOC-2/DAB2相互作用蛋白）是一种GTPase激活蛋白，除了参与其他系统的肿瘤形成和凋亡外，还参与大脑发育的各个方面。在这项研究中，我们仔细研究了Dab2IP的表达谱，并利用逆转录病毒插入LacZ编码基因捕获盒建立了Dab2IP敲低（KD）小鼠模型，研究了Dab2IP在大脑发育中的生理作用。LacZ染色显示Dab2IP在心室区、皮质板和中间区均有表达。免疫组织化学分析表明，Dab2IP蛋白定位于中间区迁移神经元的前导过程和近端胞质区。BrdU出生测定实验结合使用层特异性标记的免疫组织化学分析表明，Dab2IP对于发育中的皮层中II-IV层神经元子集的正确定位很重要。值得注意的是，Dab2IP KD小鼠大脑皮层的神经元迁移并未完全中断，迁移中断也不是严格意义上的层特异性。在此之前，我们发现Dab2IP调控皮层神经元的多极转换。其他研究表明，Rap1通过n -钙粘蛋白信号和整合素信号调节有丝分裂后迁移的神经元多极到双极形态的转变。因此，我们研究了Rap1和整合素信号是否在Dab2IP KD脑中受到影响。我们发现Dab2IP KD导致发育中的皮质中激活的Rap1和整合素水平升高。综上所述，我们的研究结果表明，Dab2IP可能通过调节Rap1和整合素信号传导，在后期出生的（II-IV层）神经元亚群的迁移和定位中发挥重要作用。
Dab2IP (DOC-2/DAB2 interacting protein) is a GTPase activating protein which is involved in various aspects of brain development in addition to its roles in tumor formation and apoptosis in other systems. In this study, we carefully examined the expression profile of Dab2IP and investigated its physiological role during brain development using a Dab2IP knock-down (KD) mouse model created by retroviral insertion of a LacZ encoding gene trapping cassette. LacZ staining revealed that Dab2IP is expressed in the ventricular zone as well as the cortical plate and the intermediate zone. Immunihistochemical analysis showed that Dab2IP protein is localized in the leading process and proximal cytoplasmic regions of migrating neurons in the intermediate zone. BrdU birthdating experiments in combination with immunohistochemical analysis using layer-specific markers showed that Dab2IP is important for proper positioning of a subset of layer II–IV neurons in the developing cortex. Notably, neuronal migration was not completely disrupted in the cerebral cortex of Dab2IP KD mice and disruption of migration was not strictly layer specific. Previously, we found that Dab2IP regulates multipolar transition in cortical neurons. Others have shown that Rap1 regulates the transition between multipolar to bipolar morphology in migrating post-mitotic neurons through N-cadherin signaling and somal translocation in the superficial layer of cortical plate through integrin signaling. Therefore, we examined whether Rap1 and integrin signaling were affected in Dab2IP KD brains. We found that Dab2IP KD resulted in higher levels of activated Rap1 and integrin in the developing cortex. Taken together, our results suggest that Dab2IP plays an important role in the migration and positioning of a sub-population of later-born (layers II–IV) neurons, likely through regulation of Rap1 and integrin signaling.
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