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  • 标题:RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly
  • 本地全文:下载
  • 作者:Chun-Hao Chen ; Albert Lee ; Chien-Po Liao
  • 期刊名称:Proceedings of the National Academy of Sciences
  • 印刷版ISSN:0027-8424
  • 电子版ISSN:1091-6490
  • 出版年度:2014
  • 卷号:111
  • 期号:46
  • 页码:16568-16573
  • DOI:10.1073/pnas.1410263111
  • 语种:English
  • 出版社:The National Academy of Sciences of the United States of America
  • 摘要:SignificanceStructural remodeling of neurons after insults to the nervous system includes retraction of the dysfunctional synaptic branches and growth of the primary neurites or new collateral branches. We find that genetic disruption of neuronal microtubules in Caenorhabditis elegans triggered structural remodeling through RHGF-1/RhoGEF, which is normally associated with and inhibited by microtubules. A conserved dual leucine zipper kinase, DLK-1, was activated by RHGF-1-dependent signaling, and activated DLK-1 was transported from distal neurite to the neuronal cell body, where it potentially altered genetic programs that enabled the destruction of injured synaptic branches and stimulated compensatory growth of the primary neurite. As microtubule, RhoGEF and DLK are conserved, the remodeling mechanisms described in this work could be a shared feature of both invertebrate and vertebrate nervous systems. Neurons remodel their connectivity in response to various insults, including microtubule disruption. How neurons sense microtubule disassembly and mount remodeling responses by altering genetic programs in the soma are not well defined. Here we show that in response to microtubule disassembly, the Caenorhabditis elegans PLM neuron remodels by retracting its synaptic branch and overextending the primary neurite. This remodeling required RHGF-1, a PDZ-Rho guanine nucleotide exchange factor (PDZ-RhoGEF) that was associated with and inhibited by microtubules. Independent of the myosin light chain activation, RHGF-1 acted through Rho-dependent kinase LET-502/ROCK and activated a conserved, retrograde DLK-1 MAPK (DLK-1/dual leucine zipper kinase) pathway, which triggered synaptic branch retraction and overgrowth of the PLM neurite in a dose-dependent manner. Our data represent a neuronal remodeling paradigm during development that reshapes the neural circuit by the coordinated removal of the dysfunctional synaptic branch compartment and compensatory extension of the primary neurite.
  • 关键词:axon retraction ; axon regeneration ; Rho signaling ; DLK ; microtubules
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