Abstract

Photoreceptor loss is a leading cause of blindness, but mechanisms underlying photoreceptor degeneration are not well understood. Treatment strategies would benefit from improved understanding of gene-expression patterns directing photoreceptor development, as many genes are implicated in both development and degeneration. Neural retina leucine zipper (NRL) is critical for rod photoreceptor genesis and degeneration, with NRL mutations known to cause enhanced S-cone syndrome and retinitis pigmentosa. While murine Nrl loss has been characterized, studies of human NRL can identify important insights for human retinal development and disease. We utilized iPSC organoid models of retinal development to molecularly define developmental alterations in a human model of NRL loss. Consistent with the function of NRL in rod fate specification, human retinal organoids lacking NRL develop S-opsin dominant photoreceptor populations. We report generation of two distinct S-opsin expressing populations in NRL null retinal organoids and identify MEF2C as a candidate regulator of cone development.

Kallman et al. showed the effect of Nrl in human PSC-derived retinal organoids. Using histological and single cell transcriptomics, they identified an intermediate “cod” subpopulation in the predominant S-opsin population. Their findings provide important insights for human retinal development and degeneration.

Details

Title
Investigating cone photoreceptor development using patient-derived NRL null retinal organoids
Author
Kallman Alyssa 1 ; Capowski, Elizabeth E 2   VIAFID ORCID Logo  ; Wang, Jie 3   VIAFID ORCID Logo  ; Kaushik, Aniruddha M 4 ; Jansen, Alex D 2 ; Edwards, Kimberly L 2 ; Chen, Liben 4 ; Berlinicke, Cynthia A 3 ; Joseph Phillips M 5 ; Pierce, Eric A 6 ; Jiang, Qian 3 ; Wang, Tza-Huei 7 ; Gamm, David M 8 ; Zack, Donald J 9   VIAFID ORCID Logo 

1  Johns Hopkins University School of Medicine, Institute of Genetic Medicine, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
2  University of Wisconsin-Madison, Waisman Center, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
3  Johns Hopkins University School of Medicine, Department of Ophthalmology, Wilmer Eye Institute, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
4  Johns Hopkins University, Department of Mechanical Engineering, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
5  University of Wisconsin-Madison, Waisman Center, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin-Madison, McPherson Eye Research Institute, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
6  Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003) 
7  Johns Hopkins University, Department of Mechanical Engineering, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University, Department of Biomedical Engineering, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
8  University of Wisconsin-Madison, Waisman Center, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin-Madison, McPherson Eye Research Institute, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675); University of Wisconsin School of Medicine and Public Health, Department of Ophthalmology and Visual Sciences, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
9  Johns Hopkins University School of Medicine, Institute of Genetic Medicine, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University School of Medicine, Department of Ophthalmology, Wilmer Eye Institute, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University School of Medicine, The Solomon H. Snyder Department of Neuroscience, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University School of Medicine, Department of Molecular Biology and Genetics, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s42003-020-0808-5
ProQuest document ID
2377660772
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.