The Photoreceptor Dystrophy and Unfolded Protein Response Regulator Gene, ATF6, Promotes Mesodermal Differentiation in Human Stem Cells

Abstract

Purpose : ATF6 encodes a transcription factor that is activated during the Unfolded Protein Response to protect cells from ER stress. Loss of function ATF6α mutations have been identified in patients with heritable photoreceptor diseases including achromatopsia and cone-rod dystrophy. A common feature in these patients is congenital malformation of the fovea, a unique region of the primate neuroretina packed with cone photoreceptors but devoid of retinal vasculature. Patients carrying mutant ATF6α alleles fail to develop this structure (foveal hypoplasia), have abrogated photoreceptor function, and have severely impaired vision from infancy. These phenotypes implicate an essential role for ATF6 during vertebrate development. Here, we investigated the function of ATF6 in early development using human stem cells undergoing differentiation into multipotent germ layers and nascent tissues.

Methods : We artificially activated ATF6 in differentiating stem cells with a recently identified small molecule ATF6 agonist, AA147. To determine changes in the RNA expression profile between treatments and cell lineage development, RNA-Seq analysis was performed. To study effects of loss of ATF6 in stem cells, we generated iPSCs from patients harboring homozygous ATF6 mutations, and we used recently identified small molecular ATF6 antagonist, Ceapin-A7.

Results : We found that ATF6 activation suppresses pluripotency, enhances differentiation, and surprisingly, guides stem cells toward mesodermal cell fates. ATF6 activation resulted in the development of endothelia cells that were able to undergo in vitro angiogenesis to form blood vessels.

Conclusions : Our findings identify a novel function for ATF6 in promoting differentiation of mesodermal tissues such as blood vessels. We suggest that ATF6, acting through its pro-angiogenic function, may be essential to create the precise vascular network in the nascent foveal region of the retina necessary for its development. When ATF6 is mutated in patients, foveal hypoplasia emerges as a consequence of abnormal retinal vasculature development.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.