Program in Neuroscience, Department of Neurobiology and Anatomy, University of Utah Medical Center, 20 North 1900 East, Salt Lake City, UT 84132, USA.
Development. 2012 Jul;139(14):2604-13. doi: 10.1242/dev.077594. Epub 2012 Jun 13.
Successful axon pathfinding requires both correct patterning of tissues, which will later harbor axonal tracts, and precise localization of axon guidance cues along these tracts at the time of axon outgrowth. Retinal ganglion cell (RGC) axons grow towards the optic disc in the central retina, where they turn to exit the eye through the optic nerve. Normal patterning of the optic disc and stalk and the expression of guidance cues at this choice point are necessary for the exit of RGC axons out of the eye. Sonic hedgehog (Shh) has been implicated in both patterning of ocular tissue and direct guidance of RGC axons. Here, we examine the precise spatial and temporal requirement for Hedgehog (Hh) signaling for intraretinal axon pathfinding and show that Shh acts to pattern the optic stalk in zebrafish but does not guide RGC axons inside the eye directly. We further reveal an interaction between the Hh and chemokine pathways for axon guidance and show that cxcl12a functions downstream of Shh and depends on Shh for its expression at the optic disc. Together, our results support a model in which Shh acts in RGC axon pathfinding indirectly by regulating axon guidance cues at the optic disc through patterning of the optic stalk.
成功的轴突寻路需要组织的正确模式化，这些组织以后将容纳轴突束，并且在轴突生长时沿着这些束精确地定位轴突导向线索。视网膜神经节细胞 (RGC) 轴突向中央视网膜的视神经盘生长，在那里它们转向通过视神经离开眼睛。视神经盘和柄的正常模式化以及在这个选择点的导向线索的表达对于 RGC 轴突离开眼睛是必要的。Sonic Hedgehog (Shh) 已被牵连到眼部组织的模式化和 RGC 轴突的直接引导中。在这里，我们研究了 Hedgehog (Hh) 信号对视网膜内轴突寻路的精确时空要求，并表明 Shh 作用于斑马鱼的视神经柄模式化，但不会直接引导 RGC 轴突在眼睛内。我们进一步揭示了 Hh 和趋化因子途径在轴突导向中的相互作用，并表明 cxcl12a 功能位于 Shh 下游，并且依赖于 Shh 在视神经盘处的表达。总之，我们的结果支持了这样一种模型，即 Shh 通过对视神经柄的模式化来间接作用于 RGC 轴突寻路，从而调节视神经盘处的轴突导向线索。
