Emc1 is essential for vision and zebrafish photoreceptor outer segment morphogenesis
Inherited retinal diseases (IRDs) are a rare group of eye disorders characterized by progressive dysfunction and degeneration of retinal cells. In this study, we characterized the raifteirí (raf) zebrafish, a novel model of inherited blindness, identified through an unbiased ENU mutagenesis screen. A mutation in the largest subunit of the endoplasmic reticulum membrane protein complex, emc1 was subsequently identified as the causative raf mutation. We sought to elucidate the cellular and molecular phenotypes in the emc1<sup>-/-</sup> knockout model and explore the association of emc1 with retinal degeneration. Visual behavior and retinal electrophysiology assays demonstrated that emc1<sup>-/-</sup> mutants had severe visual impairments. Retinal histology and morphometric analysis revealed extensive abnormalities, including thinning of the photoreceptor layer, in addition to large gaps surrounding the lens. Notably, photoreceptor outer segments were drastically smaller, outer segment protein expression was altered and hyaloid vasculature development was disrupted. Transcriptomic profiling identified cone and rod-specific phototransduction genes significantly downregulated by loss of emc1. These data shed light on why emc1 is a causative gene in inherited retinal disease and how outer segment morphogenesis is regulated.
Authors
- John O’Connor (ORCID: https://orcid.org/0000-0001-8229-8602)
- Stephen P. Carter (ORCID: https://orcid.org/0000-0002-0562-8783)
- Breandán N. Kennedy (ORCID: https://orcid.org/0000-0001-7991-4689)
- Ciara M. Walsh (ORCID: https://orcid.org/0000-0002-7873-5627)
- Margaret R. Starostik (ORCID: https://orcid.org/0000-0002-5274-2765)
- Michael R. Taylor (ORCID: https://orcid.org/0000-0003-0848-4620)
- Ross F. Collery (ORCID: https://orcid.org/0000-0002-1550-299X)
- Robert Geisler (ORCID: https://orcid.org/0000-0002-3909-8311)
- Husvinee Sundaramurthi (ORCID: https://orcid.org/0000-0002-0041-0451)
- Anand Swaroop (ORCID: https://orcid.org/0000-0002-1975-1141)
- Tess McCann (ORCID: https://orcid.org/0009-0006-2206-6221)
- Ailís Moran (ORCID: https://orcid.org/0000-0002-8706-9777)
- Sanamjeet Virdi (ORCID: https://orcid.org/0000-0002-3122-9954)
- Nora Rauch (ORCID: https://orcid.org/0000-0001-6009-5177)
- B. Sapetto-Rebow
- Milton A. English
- Yurisleidi Álvarez Álvarez (ORCID: https://orcid.org/0000-0002-7483-6279)
- Alison Reynolds (ORCID: https://orcid.org/0000-0002-3147-0094)
- Ruth Mulholland
Institutions
- University College Dublin (IE)
- Karlsruhe Institute of Technology (DE)
- National Institutes of Health (US)
- University of Wisconsin–Madison (US)
- Leibniz Institute of Virology (LIV) (DE)
- Medical College of Wisconsin (US)
- National Eye Institute (US)
Publication Details
- Journal
- The FASEB Journal
- Published
- 2024-10-03
- DOI
- https://doi.org/10.1096/fj.202401977r
- Citations
- 2
- Primary Topic
- Retinal Development and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.47
Funders
- Florida State University
- University of Washington
- Irish Research eLibrary
- Science Foundation Ireland
- National Eye Institute
- H2020 Marie Skłodowska-Curie Actions