PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling.
PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling.
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PTPN21 通过 ErbB4/NRG3 信号传导发挥促神经元存活和神经炎伸长作用。
DOI：
10.1016/j.biocel.2015.02.003
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
You
中科院分区：
文献类型：
--
作者：
J. Plani‐Lam;T. Chow;Kam;W. Chau;M. Ng;S. Bao;C. T. Ng;P. Sham;D. Shum;E. Ingley;D. Jin;You
虽然表达数量性状位点，eQTL，作为一个明确的指示基因-基因协会，挑战仍然是解开遗传变异改变基因表达的机制。在这里，我们结合eQTL和分子分析，以确定在BXD近交系小鼠脑表达数据中两个看似不相关的基因之间的关联，即Ptpn 21和Nrg 3。使用生物素标记的受体跟踪和免疫沉淀分析，我们确定PTPN 21使上游受体酪氨酸激酶ErbB 4去磷酸化，导致其下游信号传导的上调。相反，激酶死亡的ErbB 4（K751 R）或磷酸酶死亡的PTPN 21（C1108 S）突变体阻碍PTPN 21依赖性信号传导。此外，PTPN 21还诱导胚胎皮层神经元中的Elk-1活化，并且在NRG 3起始密码子上游1919 bp的区域中鉴定了一个新的Elk-1结合基序。这使得PTPN 21能够通过Elk-1促进NRG 3的表达，这为eQTL鉴定的PTPN 21-NRG 3关联提供了生化机制。在生物学上，PTPN 21积极影响皮质神经元的存活，并且与Elk-1类似，它也增加了神经炎的长度。我们的组合方法首次显示了NRG 3和PTPN 21之间在信号级联中的联系。这可能解释了为什么这两个看似无关的基因先前被确定为精神分裂症的风险基因。
Although expression quantitative trait locus, eQTL, serves as an explicit indicator of gene–gene associations, challenges remain to disentangle the mechanisms by which genetic variations alter gene expression. Here we combined eQTL and molecular analyses to identify an association between two seemingly non-associated genes in brain expression data from BXD inbred mice, namelyPtpn21andNrg3. Using biotinylated receptor tracking and immunoprecipitation analyses, we determined that PTPN21 de-phosphorylates the upstream receptor tyrosine kinase ErbB4 leading to the up-regulation of its downstream signaling. Conversely, kinase-dead ErbB4 (K751R) or phosphatase-dead PTPN21 (C1108S) mutants impede PTPN21-dependent signaling. Furthermore, PTPN21 also induced Elk-1 activation in embryonic cortical neurons and a novel Elk-1 binding motif was identified in a region located 1919 bp upstream of theNRG3initiation codon. This enables PTPN21 to promote NRG3 expression through Elk-1, which provides a biochemical mechanism for thePTPN21–NRG3association identified by eQTL. Biologically, PTPN21 positively influences cortical neuronal survival and, similar to Elk-1, it also enhances neuritic length. Our combined approaches show for the first time, a link between NRG3 and PTPN21 within a signaling cascade. This may explain why these two seemingly unrelated genes have previously been identified as risk genes for schizophrenia.
影响因子：
9.8
作者：
Chen, Pei-Lung;Avramopoulos, Dimitrios;Valle, David
通讯作者：
Valle, David
DOI：
--
发表时间：
1995
期刊：
Oncogene.
影响因子：
--
作者：
Galcheva-Gargova,Z;Theroux,SJ;Davis,RJ
通讯作者：
Davis,RJ