Instituto de Neurociencias de Alicante, CSIC & Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain.
Mol Cell Neurosci. 2010 May;44(1):30-42. doi: 10.1016/j.mcn.2010.02.001. Epub 2010 Feb 14.
Axon refinement is a necessary event for sculpting the final wiring of neural circuits. Although some factors have been identified that cause axonal arbor remodeling, the molecular pathways transducing these extracellular signals to adhesion disassembly and the cytoskeleton are poorly understood. Here we show that conditional ablation of Focal adhesion kinase (Fak) abolishes axon remodeling induced by Semaphorin-3A (Sema3A) in hippocampal neurons. Sema3A elicits divergent effects on different tyrosine residues of FAK: it increases phosphorylation of Tyr397, the kinase domain and the tyrosine residue 925, and decreases phosphorylation of Tyr407 and Tyr861. Moreover, Sema3A mediates mechanisms that contribute to the disassembly of adhesion contacts in a FAK-dependent manner: tyrosine phosphorylation of alpha-actinin and FAKY925 that decreases FAK-Paxillin interaction. Altogether, our results provide novel insights into the spatiotemporal dynamics of FAK activation mediated by Sema3A and on its interaction with its downstream effectors: Paxillin and alpha-actinin in neurons.
轴突细化是塑造神经回路最终连接的必要事件。虽然已经确定了一些导致轴突树突重塑的因素，但将这些细胞外信号转导至黏附解体和细胞骨架的分子途径还知之甚少。在这里，我们发现条件性敲除粘着斑激酶（Fak）可消除 Sema3A 在海马神经元中诱导的轴突重塑。Sema3A 对 Fak 的不同酪氨酸残基产生不同的影响：它增加了 Tyr397、激酶结构域和 Tyr925 的磷酸化，降低了 Tyr407 和 Tyr861 的磷酸化。此外，Sema3A 通过 Fak 依赖性方式介导有助于黏附接触解体的机制：α-辅肌动蛋白和 FakY925 的酪氨酸磷酸化降低了 Fak-Paxillin 相互作用。总之，我们的研究结果为 Sema3A 介导的 Fak 激活的时空动力学及其与下游效应物 Paxillin 和α-辅肌动蛋白在神经元中的相互作用提供了新的见解。
