Emc1 is essential for vision and zebrafish photoreceptor outer segment morphogenesis

• Published in: The FASEB journal 2024-10, Vol.38 (19), p.e70086-n/a
• Main Authors: McCann, Tess, Sundaramurthi, Husvinee, Walsh, Ciara, Virdi, Sanamjeet, Alvarez, Yolanda, Sapetto‐Rebow, Beata, Collery, Ross F., Carter, Stephen P., Moran, Ailis, Mulholland, Ruth, O'Connor, John J., Taylor, Michael R., Rauch, Nora, Starostik, Margaret R., English, Milton A., Swaroop, Anand, Geisler, Robert, Reynolds, Alison L., Kennedy, Breandán N.
• Format: Article
• Language: English
• Subjects: Animals; emc1; endoplasmic reticulum; inherited retinal disease; Membrane Proteins - genetics; Membrane Proteins - metabolism; Morphogenesis; Mutation; outer segment; photoreceptor; phototransduction; Retina - metabolism; Retinal Degeneration - genetics; Retinal Degeneration - metabolism; Retinal Degeneration - pathology; Retinal Photoreceptor Cell Outer Segment - metabolism; unfolded protein response; vasculature; Vision, Ocular - genetics; Vision, Ocular - physiology; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202401977R

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−/− knockout model and explore the association of emc1 with retinal degeneration. Visual behavior and retinal electrophysiology assays demonstrated that emc1−/− 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. The raifteirí (raf) zebrafish model was identified through an unbiased mutagenesis screen. Through sequencing, we discovered that the raf animals carried a homozygous mutation in the endoplasmic reticulum membrane protein complex subunit 1 (emc1). The mutants displayed a range of ocular phenotypes such as defective visual behavior, impaired visual function, altered morphology of photoreceptors, abnormal hyaloid vasculature, and decreased phototransduction gene expression.