Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403, USA.
J Neurosci. 2013 Jan 23;33(4):1509-20. doi: 10.1523/JNEUROSCI.2023-12.2013.
Work on axon growth has classically focused on understanding how extrinsic cues control growth cone dynamics independent of the cell body. However, more recently, neuron-intrinsic transcription factors have been shown to influence both normal and regenerative axon growth, suggesting that understanding their mechanism of action is of clinical importance. We are studying axon targeting in the Drosophila visual system and here show that the BTB/POZ zinc-finger transcription factor Tramtrack69 (Ttk69) plays an instructive role in inhibiting the growth of R7 photoreceptor axon terminals. Although ttk69 mutant R7 axons project to the correct medullar target layer, M6, their terminals fail to remain retinotopically restricted and instead grow laterally within M6. This overgrowth is not caused by an inability to be repelled by neighboring R7 axons or by an inability to recognize and initiate synapse formation with postsynaptic targets. The overgrowth is progressive and occurs even if contact between ttk69 mutant R7 axons and their normal target layer is disrupted. Ttk69 is first expressed in wild-type R7s after their axons have reached the medulla; ttk69 mutant R7 axon terminal overgrowth begins shortly after this time point. We find that expressing Ttk69 prematurely in R7s collapses their growth cones and disrupts axon extension, indicating that Ttk69 plays an instructive role in this process. A TGF-β/Activin pathway was shown previously to inhibit R7 axon terminal growth. We find that Ttk69 is required for normal activation of this pathway but that Ttk69 likely also inhibits R7 axon growth by a TGF-β/Activin-independent mechanism.
轴突生长的研究传统上侧重于理解外源性线索如何独立于细胞体控制生长锥的动力学。然而，最近，神经元内在的转录因子已被证明影响正常和再生轴突的生长，这表明了解其作用机制具有临床重要性。我们正在研究果蝇视觉系统中的轴突靶向，这里显示 BTB/POZ 锌指转录因子 Tramtrack69（Ttk69）在抑制 R7 光感受器轴突末端的生长中起着指导作用。尽管 ttk69 突变体 R7 轴突投射到正确的髓质靶层 M6，但它们的末端未能保持视网膜限制，而是在 M6 内横向生长。这种过度生长不是由于无法被相邻的 R7 轴突排斥，也不是由于无法识别和启动与突触后靶标的突触形成。这种过度生长是渐进的，即使在 ttk69 突变体 R7 轴突与它们的正常靶层之间的接触被破坏时也会发生。Ttk69 在野生型 R7 轴突到达髓质后首次表达；在这个时间点之后不久，ttk69 突变体 R7 轴突末端过度生长开始。我们发现，过早地在 R7 中表达 Ttk69 会使它们的生长锥崩溃并破坏轴突延伸，这表明 Ttk69 在这个过程中起着指导作用。先前的研究表明 TGF-β/Activin 途径抑制 R7 轴突末端的生长。我们发现 Ttk69 是正常激活这条途径所必需的，但 Ttk69 可能也通过 TGF-β/Activin 独立的机制抑制 R7 轴突的生长。
