PDF(Pubmed)
Abstract：
Studies on genetic robustness recently revealed transcriptional adaptation (TA) as a mechanism by which an organism can compensate for genetic mutations through activation of homologous genes. Here, we discovered that genetic mutations, introducing a premature termination codon (PTC) in the amyloid precursor protein-b (appb) gene, activated TA of two other app family members, appa and amyloid precursor-like protein-2 (aplp2), in zebrafish. The observed transcriptional response of appa and aplp2 required degradation of mutant mRNA and did not depend on Appb protein level. Furthermore, TA between amyloid precursor protein (APP) family members was observed in human neuronal progenitor cells; however, compensation was only present during early neuronal differentiation and could not be detected in a more differentiated neuronal stage or adult zebrafish brain. Using knockdown and chemical inhibition, we showed that nonsense-mediated mRNA decay (NMD) is involved in degradation of mutant mRNA and that Upf1 and Upf2, key proteins in the NMD pathway, regulate the endogenous transcript levels of appa, appb, aplp1, and aplp2 In conclusion, our results suggest that the expression level of App family members is regulated by the NMD pathway and that mutations destabilizing app/APP mRNA can induce genetic compensation by other family members through TA in both zebrafish and human neuronal progenitors.
摘要：
最近对遗传稳健性的研究表明，转录适应（TA）是生物体可以通过同源基因的激活来补偿基因突变的一种机制。这里,我们发现基因突变,在淀粉样前体蛋白-b（appb）基因中引入过早终止密码子（PTC），激活了另外两个应用程序家庭成员的TA，斑马鱼中的appa和淀粉样前体样蛋白2（aplp2）。观察到的appa和aplp2的转录反应需要突变体mRNA的降解，并且不依赖于Appb蛋白水平。此外，在人神经元祖细胞（hNPC）中观察到淀粉样前体蛋白（APP）家族成员之间的TA，然而,补偿仅在早期神经元分化期间存在，并且在分化更高的神经元阶段或成年斑马鱼大脑中无法检测到。使用击倒和化学抑制，我们表明，无义介导的mRNA衰变（NMD）参与突变mRNA的降解，Upf1和Upf2，NMD途径中的关键蛋白，调节APA的内源性转录水平，appb,aplp1和aplp2总之，我们的研究结果表明,App家族成员的表达水平受NMD通路的调控,使app/APPmRNA失稳的突变可通过TA在斑马鱼和人类神经元祖细胞中诱导其他家族成员的遗传补偿.显著性陈述增加APP水平的遗传变异与阿尔茨海默病(AD)病理生理学相关。因此,理解调节APP表达水平的机制是关键的兴趣。这里,我们确定转录适应是APP家族成员可以调节同一家族中基因表达水平以补偿另一个家族基因缺失的一种机制。在引入PTC后，补偿是通过NMD途径中介导mRNA衰减的因素驱动的。有趣的是,我们的数据还表明，即使在生理条件下，NMD监测机制也是微调APP家族成员mRNA水平的重要方面。因此，我们的发现为APP成员之间的薪酬提供了见解，并揭示了可以监管APP的新目标。
