Alternative Splicing of Disabled-1 Controls Multipolar-to-Bipolar Transition of Migrating Neurons in the Neocortex
Alternative Splicing of Disabled-1 Controls Multipolar-to-Bipolar Transition of Migrating Neurons in the Neocortex
复制标题
Disabled-1 的选择性剪接控制新皮质中迁移神经元的多极到双极转变。
DOI：
10.1093/cercor/bhx212
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发表时间：
2018-10-01
期刊：
影响因子：
3.7
通讯作者：
Gao, Zhihua
中科院分区：
文献类型：
--
作者：
Zhang, Bin;Wang, Weiwei;Gao, Zhihua
多极到双极转变（MBT）对于新皮质中神经元的迁移和定位至关重要。 ReelinDisabled-1 (Dab1) 信号在神经元迁移中发挥着关键作用，但 Dab1 如何协调调节下游分子以影响 MBT 仍不清楚。我们之前发现，选择性剪接会产生多种具有不同酪氨酸基序和招募下游效应子的能力不同的 Dab1 同工型。在这里，我们报道了 Dab1 外显子 7、8 和 9bc 的剪接动态调节新皮质中 Dab1 酪氨酸基序的包含和活性。通过子宫内电穿孔，我们发现在 WT 神经元中缺失外显子 7 和 8 或保留外显子 9bc 的 Dab1 异构体的表达会导致神经元迁移缺陷，并减弱 Dab1 酪氨酸磷酸化，破坏前导过程延伸，并使多极积累区中的多极神经元迷失方向。将规范的 Dab1 形式引入 Dab1 缺陷神经元中，但不引入那些缺失外显子 7 和 8 或保留外显子 9bc 的形式，可促进 MBT 并挽救神经元迁移缺陷，表明 Dab1 的选择性剪接可调节酪氨酸基序开关并介导皮质神经元的 MBT。我们的研究揭示了 Dab1 选择性剪接以时空方式协调控制 MBT 和神经元迁移的关键机制。
Multipolar-to-bipolar transition (MBT) is crucial for the neuronal migration and positioning in the neocortex. ReelinDisabled-1 (Dab1) signaling plays a pivotal role in neuronal migration, yet how Dab1 coordinatively regulates downstream molecules to affect MBT remains unclear. We have previously found that alternative splicing produces multiple Dab1 isoforms with different tyrosine motifs and differential ability to recruit downstream effectors. Here, we report that splicing of Dab1 exons 7 and 8 and 9bc dynamically regulates the inclusion and activities of Dab1 tyrosine motifs in the neocortex. By in utero electroporation, we show that expression of Dab1 isoforms missing exons 7 and 8 or retaining exons 9bc in WT neurons resulted in neuronal migration defects with attenuated Dab1 tyrosine phosphorylation, disrupted leading process extension, and disorientated multipolar neurons in the multipolar accumulation zone. Introducing the canonical Dab1 form, but not those missing exons 7 and 8 or retaining exons 9bc, into Dab1-deficient neurons promoted MBT and rescued neuronal migration defects, suggesting that alternative splicing of Dab1 modulates the tyrosine motif switch and mediates MBT of cortical neurons. Our study reveals a critical mechanism by which Dab1 alternative splicing coordinately controls MBT and neuronal migration in a spatiotemporal manner.