State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Cell Res. 2012 Apr;22(4):697-716. doi: 10.1038/cr.2011.172. Epub 2011 Nov 8.
Relatively little is known about the molecular mechanisms underlying spatial pathfinding in the descending serotonergic raphespinal tract (RST) in the developing spinal cord, one of the most important nerve pathways for pain, sensory and motor functions. We provide evidence that ventral floor plate-secreted Sonic hedgehog (Shh) is responsible for the establishment of decreasing gradients in both the anterior-to-posterior (A-P) and the medial-to-lateral (M-L) directions in the ventral spinal cord during serotonergic RST axon projection. Downstream components of the Shh pathway, Patched 1 (Ptch1) and Smoothened (Smo), were expressed in the serotonergic caudal raphe nuclei and enriched in the descending serotonergic RST axons. Diffusible Shh repulsion of serotonergic RST axons was shown to be mediated by Shh-Ptch1 interactions and derepression of Smo. Using a co-culture assay, we showed that A-P graded repulsion mediated by Shh signaling pushed the serotonergic axons caudally through the ventral spinal cord and M-L graded repulsion mediated by Shh signaling simultaneously restricted the serotonergic axons to the ventral and ventral-lateral funiculus. Prominent pathfinding errors of serotonergic RST axons were observed in various Shh, Ptch1 and Smo mutants. We conclude that Shh signaling-mediated multidirectional repulsion is required to push descending serotonergic RST axons in the A-P direction, and to restrict these axons to the ventral and ventral-lateral funiculus in the M-L direction. This is the first demonstration that Shh signaling-mediated multidirectional repulsion of serotonergic RST axons maintains spatial axon pathfinding in the developing spinal cord.
在发育中的脊髓中，下行 5-羟色胺能中缝脊髓束（RST）的空间寻径的分子机制相对知之甚少，它是疼痛、感觉和运动功能最重要的神经通路之一。我们提供的证据表明，腹侧基板分泌的 Sonic hedgehog（Shh）负责在 5-羟色胺能 RST 轴突投射过程中，在腹侧脊髓中建立前后（A-P）和内外（M-L）方向的递减梯度。Shh 通路的下游成分，Patched 1（Ptch1）和 Smoothened（Smo），在 5-羟色胺能尾侧中缝核中表达，并在下行 5-羟色胺能 RST 轴突中富集。表明 Shh 对 5-羟色胺能 RST 轴突的扩散性排斥是由 Shh-Ptch1 相互作用和 Smo 去抑制介导的。通过共培养测定，我们表明由 Shh 信号介导的 A-P 分级排斥推动 5-羟色胺能轴突通过腹侧脊髓向尾侧，同时由 Shh 信号介导的 M-L 分级排斥将 5-羟色胺能轴突限制在腹侧和腹侧外侧束。在各种 Shh、Ptch1 和 Smo 突变体中观察到 5-羟色胺能 RST 轴突明显的寻径错误。我们的结论是，Shh 信号介导的多方向排斥是推动下行 5-羟色胺能 RST 轴突在 A-P 方向前进所必需的，并且将这些轴突限制在 M-L 方向的腹侧和腹侧外侧束中。这是第一个证明 Shh 信号介导的 5-羟色胺能 RST 轴突的多方向排斥维持发育中脊髓的空间轴突寻径的研究。
