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The unfolded protein response regulator ATF6 promotes mesodermal differentiation

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Science Signaling  13 Feb 2018:
Vol. 11, Issue 517, eaan5785
DOI: 10.1126/scisignal.aan5785

A primitive role for ATF6

The endoplasmic reticulum (ER) mediates and monitors the folding, packaging, and transport of proteins in cells. The unfolded protein response (UPR) preserves ER homeostasis in the adult organism; however, inactivating mutations in the UPR-associated transcription factor ATF6 cause congenital vision defects, suggesting an embryonic role as well. Kroeger et al. found that ATF6 was critical to the differentiation of stem cells to the mesodermal lineage, at least in part, by promoting the growth and maturation of the ER, which presumably enables cells to stably produce the abundance of proteins necessary for development. Thus, the ER homeostasis protein in adult cells first directs ER development in embryonic cells. Activating ATF6 promoted the development of functional vascular endothelial cells from stem cells in culture dishes, suggesting that manipulating ATF6 may facilitate the production of mesodermal tissues for research or therapy.


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.

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