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The unfolded protein response regulator ATF6 promotes mesodermal differentiation
Science Signaling ( IF 6.7 ) Pub Date : 2018-02-13 , DOI: 10.1126/scisignal.aan5785
Heike Kroeger 1 , Neil Grimsey 2 , Ryan Paxman 3 , Wei-Chieh Chiang 1 , Lars Plate 3, 4 , Ying Jones 5 , Peter X. Shaw 6 , JoAnn Trejo 2 , Stephen H. Tsang 7 , Evan Powers 3 , Jeffery W. Kelly 3 , R. Luke Wiseman 3 , Jonathan H. Lin 1, 8
Affiliation  

ATF6 encodes a transcription factor that is anchored in the endoplasmic reticulum (ER) and activated during the unfolded protein response (UPR) to protect cells from ER stress. Deletion of the isoform activating transcription factor 6α (ATF6α) and its paralog ATF6β results in embryonic lethality and notochord dysgenesis in nonhuman vertebrates, and loss-of-function mutations in ATF6α are associated with malformed neuroretina and congenital vision loss in humans. These phenotypes implicate an essential role for ATF6 during vertebrate development. We investigated this hypothesis using human stem cells undergoing differentiation into multipotent germ layers, nascent tissues, and organs. We artificially activated ATF6 in stem cells with a small-molecule ATF6 agonist and, conversely, inhibited ATF6 using induced pluripotent stem cells from patients with ATF6 mutations. We found that ATF6 suppressed pluripotency, enhanced differentiation, and unexpectedly directed mesodermal cell fate. Our findings reveal a role for ATF6 during differentiation and identify a new strategy to generate mesodermal tissues through the modulation of the ATF6 arm of the UPR.



中文翻译:

展开的蛋白应答调节剂ATF6促进中胚层分化

ATF6编码转录因子,该转录因子锚定在内质网(ER)中并在未折叠的蛋白应答(UPR)期间被激活,以保护细胞免受ER应激。同种型激活转录因子6α(ATF6α)及其旁系同源物ATF6β的缺失会导致非人类脊椎动物的胚胎致死性和脊索发育不良,并且ATF6α的功能丧失突变与人类畸形的神经视网膜和先天性视力丧失有关。这些表型暗示了脊椎动物发育过程中ATF6的重要作用。我们使用人类干细胞进行分化为多能生殖层,新生组织和器官的研究,研究了这一假说。我们使用一种小分子ATF6激动剂在干细胞中人工激活了ATF6,相反,我们使用了来自多发性硬化症患者的诱导性多能干细胞来抑制ATF6。ATF6突变。我们发现,ATF6抑制了多能性,增强了分化,并出乎意料地引导了中胚层细胞的命运。我们的发现揭示了ATF6在分化过程中的作用,并确定了通过调节UPR的ATF6臂产生中胚层组织的新策略。

更新日期:2018-02-14
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