A midline switch of receptor processing regulates commissural axon guidance in vertebrates
A midline switch of receptor processing regulates commissural axon guidance in vertebrates
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DOI：
10.1101/gad.542510
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发表时间：
2010-02-15
影响因子：
10.5
通讯作者：
Castellani, Valerie
中科院分区：
文献类型：
--
作者：
Nawabi, Homaira;Briancon-Marjollet, Anne;Castellani, Valerie
连合轴突的指导需要复杂的调制生长锥敏感性中线衍生的线索，但在脊椎动物的潜在机制仍然在很大程度上未知。通过使用离体和体内方法的组合，我们发现了控制对中线驱避剂Semaphorin 3B（Sema 3B）的响应的获得的分子途径。首先，我们提供的证据表明，Semaphorin 3B/丛蛋白-A1信号参与指导连合预测在脊椎动物腹侧中线。其次，我们发现，在交叉前阶段，连合神经元合成的Neuropilin-2和丛蛋白-A1 Semaphorin 3B受体亚基，但丛蛋白-A1的表达被阻止钙蛋白酶1介导的处理，导致沉默连合反应。第三，我们报告说，在地板（FP）的生长，钙蛋白酶1活性受到抑制的本地信号，允许丛蛋白-A1的积累在生长锥和敏化Sema 3B。最后，我们表明FP提示NrCAM介导丛状蛋白-A1加工的开关，潜在的生长锥敏化Sema 3B。这揭示了引导受体处理的路径依赖性调节是调节中间目标引导决策的一种新机制。
Commissural axon guidance requires complex modulations of growth cone sensitivity to midline-derived cues, but underlying mechanisms in vertebrates remain largely unknown. By using combinations of ex vivo and in vivo approaches, we uncovered a molecular pathway controlling the gain of response to a midline repellent, Semaphorin3B (Sema3B). First, we provide evidence that Semaphorin3B/Plexin-A1 signaling participates in the guidance of commissural projections at the vertebrate ventral midline. Second, we show that, at the precrossing stage, commissural neurons synthesize the Neuropilin-2 and Plexin-A1 Semaphorin3B receptor subunits, but Plexin-A1 expression is prevented by a calpain1-mediated processing, resulting in silencing commissural responsiveness. Third, we report that, during floor plate (FP) in-growth, calpain1 activity is suppressed by local signals, allowing Plexin-A1 accumulation in the growth cone and sensitization to Sema3B. Finally, we show that the FP cue NrCAM mediates the switch of Plexin-A1 processing underlying growth cone sensitization to Sema3B. This reveals pathway-dependent modulation of guidance receptor processing as a novel mechanism for regulating guidance decisions at intermediate targets.