University of Lyon, University of Lyon 1, Claude Bernard Lyon1, CGMC, UMR, CNRS 5534, F-69000 Lyon, France.
Genes Dev. 2010 Feb 15;24(4):396-410. doi: 10.1101/gad.542510.
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.
连接轴突的导向需要对来自中线的信号进行复杂的生长锥敏感性调节，但脊椎动物的潜在机制在很大程度上仍然未知。通过使用组合的离体和体内方法，我们揭示了控制对中线排斥物 Semaphorin3B（Sema3B）反应增益的分子途径。首先，我们提供了证据表明 Sema3B/Plexin-A1 信号参与了脊椎动物腹侧中线处连接轴突投射的导向。其次，我们表明，在交叉前阶段，连接神经元合成神经纤毛蛋白-2 和 Plexin-A1 Sema3B 受体亚基，但 Plexin-A1 表达被钙蛋白酶 1 介导的加工所阻止，导致连接反应性沉默。第三，我们报告说，在基板（FP）向内生长过程中，钙蛋白酶 1 活性被局部信号抑制，允许 Plexin-A1 在生长锥中积累并对 Sema3B 敏感化。最后，我们表明，基板线索 NrCAM 介导了生长锥对 Sema3B 敏感性化的 Plexin-A1 加工的转换。这揭示了导向受体加工的途径依赖性调节作为调节中间靶标导向决策的新机制。
