Functional dissection of reelin signaling by site-directed disruption of disabled-1 adaptor binding to apolipoprotein E receptor 2: Distinct roles in development and synaptic plasticity
Functional dissection of reelin signaling by site-directed disruption of disabled-1 adaptor binding to apolipoprotein E receptor 2: Distinct roles in development and synaptic plasticity
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DOI：
10.1523/jneurosci.4566-05.2006
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发表时间：
2006-02-15
影响因子：
5.3
通讯作者：
Herz, J
中科院分区：
文献类型：
--
作者：
Beffert, U;Durudas, A;Herz, J
Reelin信号通路控制人类和小鼠大脑发育过程中神经元的定位，以及成年后长时程增强(LTP)和行为的调节。Reelin通过结合两个跨膜受体，载脂蛋白E受体2(ApoER2)和极低密度脂蛋白受体来传递信号。在Reelin与受体结合后，细胞内的失活-1(Dab1)蛋白结合到受体的细胞质尾部，在酪氨酸残基上被磷酸化，启动了一系列信号级联反应，其中包括Src家族激酶和Akt的激活。在这里，我们创建了一个突变小鼠系(ApoER2 EIG)，其中ApoER2 NFDNPVY基序已被改变为EIGNPVY，以破坏ApoER2-Dab1的相互作用，以进一步研究Reelin信号在发育和成人脑中的作用。利用重组Reelin刺激的原代神经元培养，我们发现正常的Reelin信号需要野生型NFDNPVY序列，很可能是ApoER2与Dab1的相互作用。此外，对海马、皮质和小脑分层的研究表明，ApoER2的NFDNPVY序列对于大脑发育过程中正常的神经元定位是必不可少的。成年ApoER2 EIG小鼠表现出严重的LTP和行为异常，这与缺乏ApoER2的小鼠不同。在ApoER2 EIG切片中，LTP在30分钟内降解到基线，这在Reelin存在的情况下被阻止。总之，这些发现强调了成人大脑中Reelin信号的复杂性，这可能需要多个接头蛋白与ApoER2的细胞内结构域相互作用。
The Reelin signaling pathway controls neuronal positioning in human and mouse brain during development as well as modulation of long-term potentiation (LTP) and behavior in the adult. Reelin signals by binding to two transmembrane receptors, apolipoprotein E receptor 2 (Apoer2) and very-low-density lipoprotein receptor. After Reelin binds to the receptors, Disabled-1 (Dab1), an intracellular adaptor protein that binds to the cytoplasmic tails of the receptors, becomes phosphorylated on tyrosine residues, initiating a signaling cascade that includes activation of Src-family kinases and Akt. Here, we have created a line of mutant mice (Apoer2 EIG) in which the Apoer2 NFDNPVY motif has been altered to EIGNPVY to disrupt the Apoer2-Dab1 interaction to further study Reelin signaling in development and adult brain. Using primary neuronal cultures stimulated with recombinant Reelin, we find that normal Reelin signaling requires the wild-type NFDNPVY sequence and likely the interaction of Apoer2 with Dab1. Furthermore, examination of hippocampal, cortical, and cerebellar layering reveals that the NFDNPVY sequence of Apoer2 is indispensable for normal neuronal positioning during development of the brain. Adult Apoer2 EIG mice display severe abnormalities in LTP and behavior that are distinct from those observed for mice lacking Apoer2. In Apoer2 EIG slices, LTP degraded to baseline within 30 min, and this was prevented in the presence of Reelin. Together, these findings emphasize the complexity of Reelin signaling in the adult brain, which likely requires multiple adaptor protein interactions with the intracellular domain of Apoer2.