Thyroid hormone signaling specifies cone subtypes in human retinal organoids

Kiara C. Eldred, Sarah E. Hadyniak, Katarzyna A. Hussey, Boris Brennerman, Pingwu Zhang, Xitiz Chamling, Valentin M. Sluch, Derek S. Welsbie, Samer Hattar, James Taylor, Karl Wahlin, Donald J. Zack, Robert J. Johnston

Research output: Contribution to journalArticlepeer-review

Abstract

The mechanisms underlying the specification of diverse neuronal subtypes within the human nervous system are largely unknown. The blue (shortwavelength/S), green (medium-wavelength/M) and red (long-wavelength/L) cone photoreceptors of the human retina enable high-acuity daytime vision and trichromatic color perception. Cone subtypes are specified in a poorly understood two-step process, with a first decision between S and L/M fates, followed by a decision between L and M fates. To determine the mechanism controlling S vs. L/M fates, we studied the differentiation of human retinal organoids. We found that human organoids and retinas have similar distributions, gene expression profiles, and morphologies of cone subtypes. We found that S cones are specified first, followed by L/M cones, and that thyroid hormone signaling is necessary and sufficient for this temporal switch. Temporally dynamic expression of thyroid hormone degrading and activating proteins supports a model in which the retina itself controls thyroid hormone levels, ensuring low signaling early to specify S cones and high signaling late to produce L/M cones. This work establishes organoids as a model for determining the mechanisms of cell fate specification during human development. One sentence summary Cone specification in human organoids

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Jun 30 2018

Keywords

  • cone cell
  • CRISPR/Cas9
  • DIO2
  • DIO3
  • human retina
  • opsin
  • organoid
  • photoreceptor
  • T3
  • T4
  • Thrβ
  • thyroid hormone receptor beta

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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