Growth cone MKK7 mRNA targeting regulates MAP1b-dependent microtubule bundling to control neurite elongation.
Growth cone MKK7 mRNA targeting regulates MAP1b-dependent microtubule bundling to control neurite elongation.
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DOI：
10.1371/journal.pbio.1001439
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
Pertz O
中科院分区：
文献类型：
--
作者：
Feltrin D;Fusco L;Witte H;Moretti F;Martin K;Letzelter M;Fluri E;Scheiffele P;Pertz O
MKK7 mRNA的生长锥定位将MKK7蛋白在转录控制中的经典功能转换为调节神经元生长所必需的微管。神经元中的局部mRNA翻译主要在轴突引导和突触形成过程中进行研究，但在最初的神经突生长过程中没有研究。我们对神经突富集的mRNA进行了全基因组筛选，并鉴定了编码促分裂原活化蛋白激酶激酶7（MKK7）的mRNA，MKK7是Jun激酶（JNK）的MAP激酶激酶（MAPKK）。我们发现MKK7 mRNA定位于生长锥，在那里它有可能被翻译。然后MKK7在神经突轴中特异性磷酸化，在那里它是由双亮氨酸拉链激酶（DLK）、MKK7和JNK1组成的MAP激酶信号传导模块的一部分。这触发Map1b磷酸化调节微管束，导致神经突伸长。我们提出了一个模型，其中MKK7 mRNA的定位和翻译在生长锥允许的机制，以定位JNK信号在轴突轴，并具体地将其连接到微管束的调节。同时，这使激活的JNK与其核转位和转录激活相关的功能解偶联。mRNA转录物通常在胞质溶胶中翻译成蛋白质。然而，一些mRNA首先被转运到特定的亚细胞区域，在那里它们被翻译以执行定位功能。这在高度极化的细胞如神经元中尤其重要。在这里，我们发现，转录编码的信号分子促分裂原活化蛋白激酶7（MKK7）定位于生长锥的神经元过程，在那里它最有可能被翻译。这是令人惊讶的，因为MKK7已经与响应于细胞损伤的细胞核中的转录激活相关联。我们发现，生长锥MKK7 mRNA转录本的定位，并可能在这个亚细胞定位的翻译，允许MKK7蛋白转换其功能和调节微管细胞骨架，这是必要的神经元生长。这是通过在神经突中形成空间调节的MKK7信号结构域来实现的，该结构域执行这种高度专门化的功能。
Growth cone localization of MKK7 mRNA switches the classic function of MKK7 protein in transcriptional control to regulation of microtubules necessary for neuronal outgrowth. Local mRNA translation in neurons has been mostly studied during axon guidance and synapse formation but not during initial neurite outgrowth. We performed a genome-wide screen for neurite-enriched mRNAs and identified an mRNA that encodes mitogen-activated protein kinase kinase 7 (MKK7), a MAP kinase kinase (MAPKK) for Jun kinase (JNK). We show that MKK7 mRNA localizes to the growth cone where it has the potential to be translated. MKK7 is then specifically phosphorylated in the neurite shaft, where it is part of a MAP kinase signaling module consisting of dual leucine zipper kinase (DLK), MKK7, and JNK1. This triggers Map1b phosphorylation to regulate microtubule bundling leading to neurite elongation. We propose a model in which MKK7 mRNA localization and translation in the growth cone allows for a mechanism to position JNK signaling in the neurite shaft and to specifically link it to regulation of microtubule bundling. At the same time, this uncouples activated JNK from its functions relevant to nuclear translocation and transcriptional activation. MRNA transcripts are usually translated into proteins in the cytosol. Some mRNAs, however, are first transported to specific subcellular regions where they are translated to perform localized functions. This is especially important in highly polarized cells such as neurons. Here, we find that a transcript encoding the signaling molecule mitogen-activated protein kinase kinase 7 (MKK7) localizes to the growth cone of neuronal processes, where it most likely is translated. This is surprising, because MKK7 has been linked to activation of transcription in the nucleus in response to cellular insults. We find that growth cone MKK7 mRNA transcript localization, and potentially its translation at this subcellular localization, allows the MKK7 protein to switch its function and regulate the microtubule cytoskeleton, which is necessary for neuronal outgrowth. This occurs through the formation of a spatially regulated MKK7 signaling domain in the neurite that performs this highly specialized function.
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影响因子：
9.2
作者：
Dajas-Ballador, Federico;Jones, Emma V.;Whitmarsh, Alan J.
通讯作者：
Whitmarsh, Alan J.
影响因子：
64.5
作者：
de Hoog, CL;Foster, LJ;Mann, M
通讯作者：
Mann, M
影响因子：
48
作者：
Barrett, Lindy E.;Sul, Jai-Yoon;Eberwine, James H.
通讯作者：
Eberwine, James H.
DOI：
10.1073/pnas.0909671107
发表时间：
2010-03-23
影响因子：
11.1
作者：
Fosbrink, Matthew;Aye-Han, Nwe-Nwe;Zhang, Jin
通讯作者：
Zhang, Jin
影响因子：
4.5
作者：
Gumy, Laura F.;Yeo, Giles S. H.;Fawcett, James W.
通讯作者：
Fawcett, James W.