Martinez Jose A, Kobayashi Masaki, Krishnan Anand, Webber Christine, Christie Kimberly, Guo GuiFang, Singh Vandana, Zochodne Douglas W
Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Exp Neurol. 2015 Sep;271:493-505. doi: 10.1016/j.expneurol.2015.07.018. Epub 2015 Jul 22.
Intrinsic molecular determinants of neurodevelopmental outcomes assume new, albeit related roles during adult neural regeneration. Here we studied and identified a facilitatory role for Sonic hedgehog protein (Shh), a morphogen that influences motor neuron floor plate architecture, during adult peripheral neuron regeneration. Shh and its receptors were expressed in adult dorsal root ganglia (DRG) neurons, axons and glia and trended toward higher levels following axotomy injury. Knockdown of Shh in adult sensory neurons resulted in decreased outgrowth and branching in vitro, identifying a role for Shh in facilitating outgrowth. The findings argued for an intrinsic action to support neuron regeneration. Support of advancement and turning however, were not identified in adult sensory neuron growth cones in response to local extrinsic gradients of Shh. That intrinsic Shh supported the regrowth of peripheral nerves after injury was confirmed by the analysis of axon regrowth from the proximal stumps of transected sciatic nerves. By exposing regenerating axons to local infusions of Shh siRNA in vivo within a conduit bridging the transected proximal and distal stumps, we achieved local knockdown of Shh. In response, there was attenuated axonal and Schwann cell outgrowth beyond the transection zone. Unlike its role during neurodevelopment, Shh facilitates but does not confer regenerative outgrowth properties to adult neurons alone. Exploring the differing properties of morphogens and related proteins in the adult nervous system identifies new and important roles for them.
神经发育结果的内在分子决定因素在成体神经再生过程中发挥着新的、尽管相关的作用。在此，我们研究并确定了音猬因子（Shh）在成体周围神经元再生过程中的促进作用，Shh是一种影响运动神经元底板结构的形态发生素。Shh及其受体在成体背根神经节（DRG）神经元、轴突和神经胶质细胞中表达，在轴突切断损伤后表达水平呈上升趋势。在成体感觉神经元中敲低Shh会导致体外生长和分支减少，这表明Shh在促进生长方面发挥作用。这些发现支持了一种支持神经元再生的内在作用。然而，在成体感觉神经元生长锥中，未发现其对局部外源性Shh梯度有促进延伸和转向的作用。通过对横断坐骨神经近端残端的轴突再生进行分析，证实了内在的Shh支持损伤后周围神经的再生。通过在连接横断近端和远端残端的导管内对再生轴突进行体内局部注射Shh siRNA，我们实现了Shh的局部敲低。相应地，在横断区域以外，轴突和雪旺细胞的生长减弱。与它在神经发育过程中的作用不同，Shh促进但不单独赋予成体神经元再生生长特性。探索成体神经系统中形态发生素和相关蛋白的不同特性，揭示了它们新的重要作用。
