Grb4 and GIT1 transduce ephrinB reverse signals modulating spine morphogenesis and synapse formation
Grb4 and GIT1 transduce ephrinB reverse signals modulating spine morphogenesis and synapse formation
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DOI：
10.1038/nn1858
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发表时间：
2007-03-01
影响因子：
25
通讯作者：
Acker-Palmer, Amparo
中科院分区：
文献类型：
--
作者：
Segura, Inmaculada;Essmann, Clara L.;Acker-Palmer, Amparo
树突棘是从接受兴奋性输入的树突出现的小突起。脊柱形态发生的过程发生在发育中的大脑和突触可塑性。调节细胞骨架的分子参与棘的形成和维持。在这里，我们表明，Eph受体，ephrinBs的跨膜配体的反向信号，是正确的脊柱形态所需的。ephrinBs这种功能的分子机制涉及含有SH2和SH3结构域的衔接蛋白Grb4和G蛋白偶联受体激酶相互作用蛋白（GIT）1。Grb4通过其SH2结构域与GIT 1的突触定位结构域中的Tyr392结合。Tyr392的磷酸化和GIT 1向突触的募集受ephrinB激活的调节。在培养的大鼠海马神经元中，这一通路的中断会损害棘形态发生和突触形成。因此，我们显示了一个重要的作用ephrinB反向信号在脊柱形成，并绘制了下游通路参与这一过程。
Dendritic spines are small protrusions emerging from dendrites that receive excitatory input. The process of spine morphogenesis occurs both in the developing brain and during synaptic plasticity. Molecules regulating the cytoskeleton are involved in spine formation and maintenance. Here we show that reverse signaling by the transmembrane ligands for Eph receptors, ephrinBs, is required for correct spine morphogenesis. The molecular mechanism underlying this function of ephrinBs involves the SH2 and SH3 domain-containing adaptor protein Grb4 and the G protein-coupled receptor kinase-interacting protein (GIT) 1. Grb4 binds by its SH2 domain to Tyr392 in the synaptic localization domain of GIT1. Phosphorylation of Tyr392 and the recruitment of GIT1 to synapses are regulated by ephrinB activation. Disruption of this pathway in cultured rat hippocampal neurons impairs spine morphogenesis and synapse formation. We thus show an important role for ephrinB reverse signaling in spine formation and have mapped the downstream pathway involved in this process.