PT  - JOURNAL ARTICLE
AU  - Kiara C. Eldred
AU  - Sarah E. Hadyniak
AU  - Katarzyna A. Hussey
AU  - Boris Brennerman
AU  - Pingwu Zhang
AU  - Xitiz Chamling
AU  - Valentin M. Sluch
AU  - Derek S. Welsbie
AU  - Samer Hattar
AU  - James Taylor
AU  - Karl Wahlin
AU  - Donald J. Zack
AU  - Robert J. Johnston, Jr.
TI  - Thyroid hormone signaling specifies cone subtypes in human retinal organoids
AID  - 10.1101/359950
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 359950
4099  - http://biorxiv.org/content/early/2018/06/30/359950.short
4100  - http://biorxiv.org/content/early/2018/06/30/359950.full
AB  - 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