Terminal neuron localization to the upper cortical plate is controlled by the transcription factor NEUROD2
Terminal neuron localization to the upper cortical plate is controlled by the transcription factor NEUROD2
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DOI：
10.1038/s41598-019-56171-x
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发表时间：
2019-12-23
影响因子：
4.6
通讯作者：
Ince-Dunn, Gulayse
中科院分区：
文献类型：
--
作者：
Guzelsoy, Gizem;Akkaya, Cansu;Ince-Dunn, Gulayse
哺乳动物大脑皮层的兴奋性神经元分为六个功能层，其特征在于独特的连接模式以及独特的生理和形态特性。皮质层是在高度调控的迁移过程之后出现的，在该过程中，细胞从更深的增殖区向浅层移动。重要的是，这种径向迁移过程的缺陷与神经发育和精神疾病有关。在这里，我们报告在迁移的最后阶段，转录因子神经源性分化 2 (Neurod2) 有助于皮质板内的终末细胞定位。在小鼠中，在子宫内敲低 Neurod2 导致位于发育中皮质最上部区域（也称为原始皮质区）的神经元数量减少。我们对发育中皮层中受 NEUROD2 调节的基因进行 ChIP-Seq 和 RNA-Seq 分析，确定了许多在 Reelin 信号传导（神经元迁移的关键调节因子）中具有已知作用的关键靶基因。我们对编码细胞外配体 REELIN 的 Reln 基因的调控进行了重点分析，发现 NEUROD2 与多个内含子中的保守 E-box 元件结合。此外，我们证明初级皮质神经元中 NEUROD2 的敲低导致 Reln 基因表达在 mRNA 水平上大幅增加，以及在蛋白质水平上略有上调。这些数据揭示了 NEUROD2 在神经元迁移后期的新作用，我们对其基因组靶标的分析提供了在皮质层压中具有潜在作用的新基因。
Excitatory neurons of the mammalian cerebral cortex are organized into six functional layers characterized by unique patterns of connectivity, as well as distinctive physiological and morphological properties. Cortical layers appear after a highly regulated migration process in which cells move from the deeper, proliferative zone toward the superficial layers. Importantly, defects in this radial migration process have been implicated in neurodevelopmental and psychiatric diseases. Here we report that during the final stages of migration, transcription factor Neurogenic Differentiation 2 (Neurod2) contributes to terminal cellular localization within the cortical plate. In mice, in utero knockdown of Neurod2 resulted in reduced numbers of neurons localized to the uppermost region of the developing cortex, also termed the primitive cortical zone. Our ChIP-Seq and RNA-Seq analyses of genes regulated by NEUROD2 in the developing cortex identified a number of key target genes with known roles in Reelin signaling, a critical regulator of neuronal migration. Our focused analysis of regulation of the Reln gene, encoding the extracellular ligand REELIN, uncovered NEUROD2 binding to conserved E-box elements in multiple introns. Furthermore, we demonstrate that knockdown of NEUROD2 in primary cortical neurons resulted in a strong increase in Reln gene expression at the mRNA level, as well as a slight upregulation at the protein level. These data reveal a new role for NEUROD2 during the late stages of neuronal migration, and our analysis of its genomic targets offers new genes with potential roles in cortical lamination.