Zhang Jinhua, Jin Zhe, Bao Zheng-Zheng
Department of Medicine and Cell Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Development. 2004 Apr;131(7):1553-62. doi: 10.1242/dev.01041. Epub 2004 Feb 25.
The targeting of retinal ganglion axons toward the optic disc is the first step in axon pathfinding in the visual system. The molecular mechanisms involved in guiding the retinal axons to project towards the optic disc are not well understood. We report that a gene encoding a zinc-finger transcription factor, Zic3, is expressed in a periphery-high and center-low gradient in the retina at the stages of active axon extension inside the retina. The gradient expression of Zic3 recedes towards the periphery over the course of development, correlating with the progression of retinal cell differentiation and axonogenesis. Disruption of gradient expression of Zic3 by retroviral overexpression resulted in mis-targeting of retinal axons and some axons misrouted to the sub-retinal space at the photoreceptor side of the retina. Misexpression of Zic3 did not affect neurogenesis or differentiation inside the retina, or grossly alter retinal lamination. By stripe assay, we show that misexpression of Zic3 may induce the expression of an inhibitory factor to the retinal axons. Zic3 appears to play a role in intra-retinal axon targeting, possibly through regulation of the expression of specific downstream genes involved in axon guidance.
视网膜神经节细胞轴突向视盘的靶向投射是视觉系统中轴突寻路的第一步。目前对于引导视网膜轴突向视盘投射的分子机制尚不清楚。我们报道，在视网膜内轴突活跃延伸阶段，一个编码锌指转录因子Zic3的基因在视网膜中呈外周高、中央低的梯度表达。随着发育进程，Zic3的梯度表达向周边逐渐减弱，这与视网膜细胞分化和轴突发生的进程相关。通过逆转录病毒过表达破坏Zic3的梯度表达，导致视网膜轴突靶向错误，一些轴突错误地导向视网膜感光细胞侧的视网膜下间隙。Zic3的错误表达不影响视网膜内的神经发生或分化，也未显著改变视网膜分层。通过条带分析，我们发现Zic3的错误表达可能诱导了一种对视网膜轴突具有抑制作用的因子的表达。Zic3似乎在视网膜内轴突靶向中发挥作用，可能是通过调控参与轴突导向的特定下游基因的表达来实现的。
