July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
The Photoreceptor Dystrophy and Unfolded Protein Response Regulator Gene, ATF6, Promotes Mesodermal Differentiation in Human Stem Cells
Author Affiliations & Notes
  • Heike Kroeger
    Pathology, University of California San Diego, La Jolla, California, United States
  • Neil Grimsey
    Pharmacology, University of California San Diego, La Jolla, California, United States
  • Ryan J Paxman
    Molecular Medicine, SCRIPPS Research Institute, La Jolla, California, United States
  • Wei-Chieh Chiang
    Pathology, University of California San Diego, La Jolla, California, United States
  • Lars Plate
    Chemistry and Biological Sciences, Vanderbilt University,, Nashville, Tennessee, United States
  • Ying Jones
    Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, United States
  • Peter Shaw
    Opthalmology, University of California San Diego, La Jolla, California, United States
  • JoAnn Trejo
    Pharmacology, University of California San Diego, La Jolla, California, United States
  • Stephen Tsang
    Ophthalmology, Pathology and Cell Biology, Jonas Children’s Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, Edward S. Harkness Eye Institute, New York Presbyterian Hospital, Columbia University, New York, New York, United States
  • Evan Powers
    Molecular Medicine, SCRIPPS Research Institute, La Jolla, California, United States
  • Jeffrey Kelly
    Molecular Medicine, SCRIPPS Research Institute, La Jolla, California, United States
  • R. Luke Wiseman
    Molecular Medicine, SCRIPPS Research Institute, La Jolla, California, United States
  • Jonathan H Lin
    Pathology, University of California San Diego, La Jolla, California, United States
    VA San Diego Healthcare System, San Diego, California, United States
  • Footnotes
    Commercial Relationships   Heike Kroeger, None; Neil Grimsey, None; Ryan Paxman, SCRIPPS Research Institute (P); Wei-Chieh Chiang, None; Lars Plate, SCRIPPS Research Institute (P); Ying Jones, None; Peter Shaw, None; JoAnn Trejo, None; Stephen Tsang, None; Evan Powers, None; Jeffrey Kelly, SCRIPPS Research Institute (P); R. Luke Wiseman, SCRIPPS Research Institute (P); Jonathan Lin, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4587. doi:
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      Heike Kroeger, Neil Grimsey, Ryan J Paxman, Wei-Chieh Chiang, Lars Plate, Ying Jones, Peter Shaw, JoAnn Trejo, Stephen Tsang, Evan Powers, Jeffrey Kelly, R. Luke Wiseman, Jonathan H Lin; The Photoreceptor Dystrophy and Unfolded Protein Response Regulator Gene, ATF6, Promotes Mesodermal Differentiation in Human Stem Cells. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4587.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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