RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly
RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly
复制标题
DOI：
10.1073/pnas.1410263111
复制
发表时间：
2014-11-18
影响因子：
11.1
通讯作者：
Pan, Chun-Liang
中科院分区：
文献类型：
--
作者：
Chen, Chun-Hao;Lee, Albert;Pan, Chun-Liang
神经元对包括微管破裂在内的各种损伤做出反应，重塑它们的连接性。神经元如何通过改变胞体中的遗传程序来感知微管分解和安装重塑反应还没有很好的定义。在这里，我们展示了对微管解体的反应，秀丽线虫的PLM神经元通过收缩其突触分支和过度伸展初级轴突来重塑。这种重塑需要RHGF-1，一种与微管相关并被微管抑制的PDZ-Rho鸟嘌呤核苷酸交换因子(PDZ-Rhogef)。RHGF-1不依赖肌球蛋白轻链的激活，而是通过Rho依赖的激酶let-502/ROCK激活保守的、逆行的DLK-1 MAPK(DLK-1/双亮氨酸拉链激酶)通路，该通路以剂量依赖的方式引发突触分支收缩和PLM突起的过度生长。我们的数据代表了发育过程中的神经元重塑范式，通过协调移除功能障碍的突触支室和初级轴突的代偿性延伸来重塑神经电路。
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.