Comparative study of visual dysfunctions in 6–10-year-old very preterm- and full-term-born children

et al. 2018

Preprint

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 summaryCone specification in human organoids

Section: Dynamic Expression Of Thyroid Hormone-regulating Genes Durinsupporting

confidence: 88%

Thyroid hormone signaling specifies cone subtypes in human retinal organoids

Eldred

et al. 2018

Preprint

“…Our studies identify temporal regulation of thyroid hormone signaling as a mechanism that controls cone subtype specification in humans. Consistent with our findings, preterm human infants with low T3/T4 have an increased incidence of color vision defects (49)(50)(51)(52). Moreover, our identification of a mechanism that generates one cone subtype while suppressing the other, coupled with successful transplantation and incorporation of stem cell-derived photoreceptors in mice (53)(54)(55)(56), suggests that the promise of therapies to treat human diseases such as color blindness, retinitis pigmentosa, and macular degeneration will be achieved in the near future.…”

Section: Dynamic Expression Of Thyroid Hormone-regulating Genes Durin...supporting

confidence: 86%

Thyroid hormone signaling specifies cone subtypes in human retinal organoids

Eldred

et al. 2018

Science

221

164

The mechanisms underlying specification of neuronal subtypes within the human nervous system are largely unknown. The blue (S), green (M), and red (L) cones of the retina enable high-acuity daytime and color vision. To determine the mechanism that controls S versus L/M fates, we studied the differentiation of human retinal organoids. Organoids and retinas have similar distributions, expression profiles, and morphologies of cone subtypes. S cones are specified first, followed by L/M cones, and thyroid hormone signaling controls this temporal switch. Dynamic expression of thyroid hormone–degrading and –activating proteins within the retina ensures 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 mechanisms of human development with promising utility for therapeutics and vision repair.

“…Consistent with these studies in model organisms, clinical evidence supports a role for thyroid hormone signaling in cone subtype differentiation in the human retina. Premature infants with low ratios of T3 to T4 have an increased incidence of color vision deficiencies ( Dowdeswell et al, 1995 ; Rovet and Simic, 2008 ; Simic et al, 2010 ; Yassin et al, 2019 ). Additionally, patients with mutations in THRB display altered color perception ( Weiss et al, 2012 ).…”

Section: Photoreceptor Subtype Specificationmentioning

confidence: 99%

Patterning and Development of Photoreceptors in the Human Retina

Johnston

2022

Front. Cell Dev. Biol.

Humans rely on visual cues to navigate the world around them. Vision begins with the detection of light by photoreceptor cells in the retina, a light-sensitive tissue located at the back of the eye. Photoreceptor types are defined by morphology, gene expression, light sensitivity, and function. Rod photoreceptors function in low-light vision and motion detection, and cone photoreceptors are responsible for high-acuity daytime and trichromatic color vision. In this review, we discuss the generation, development, and patterning of photoreceptors in the human retina. We describe our current understanding of how photoreceptors are patterned in concentric regions. We conclude with insights into mechanisms of photoreceptor differentiation drawn from studies of model organisms and human retinal organoids.