Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, United States.
Neuroscience Graduate Program, Oregon Health & Science University, Portland, United States.
Elife. 2019 Sep 2;8:e46092. doi: 10.7554/eLife.46092.
The trafficking mechanisms and transcriptional targets downstream of long-range neurotrophic factor ligand/receptor signaling that promote axon growth are incompletely understood. Zebrafish carrying a null mutation in a neurotrophic factor receptor, Ret, displayed defects in peripheral sensory axon growth cone morphology and dynamics. Ret receptor was highly enriched in sensory pioneer neurons and Ret51 isoform was required for pioneer axon outgrowth. Loss-of-function of a cargo adaptor, Jip3, partially phenocopied Ret axonal defects, led to accumulation of activated Ret in pioneer growth cones, and reduced retrograde Ret51 transport. Jip3 and Ret51 were also retrogradely co-transported, ultimately suggesting Jip3 is a retrograde adapter of active Ret51. Finally, loss of Ret reduced transcription and growth cone localization of Myosin-X, an initiator of filopodial formation. These results show a specific role for Ret51 in pioneer axon growth, and suggest a critical role for long-range retrograde Ret signaling in regulating growth cone dynamics through downstream transcriptional changes.
长程神经营养因子配体/受体信号促进轴突生长的转运机制和下游转录靶标尚不完全清楚。携带神经营养因子受体 Ret 缺失突变的斑马鱼在外周感觉轴突生长锥形态和动力学方面存在缺陷。Ret 受体在感觉先驱神经元中高度富集，Ret51 同工型对于先驱轴突的生长至关重要。货物衔接蛋白 Jip3 的功能丧失部分模拟了 Ret 轴突缺陷，导致激活的 Ret 在先驱生长锥中积累，并减少了逆行的 Ret51 运输。Jip3 和 Ret51 也被逆行共转运，最终表明 Jip3 是活跃的 Ret51 的逆行衔接蛋白。最后，Ret 的缺失减少了肌球蛋白-X 的转录和生长锥定位，肌球蛋白-X 是形成丝状伪足的启动子。这些结果表明 Ret51 在先驱轴突生长中具有特定作用，并表明长程逆行 Ret 信号在通过下游转录变化调节生长锥动力学方面具有关键作用。
