Tyro3 modulates Mertk-associated retinal degeneration
Open accessAbstract
Inherited photoreceptor degenerations (IPDs) are the most genetically heterogeneous of Mendelian diseases. Many IPDs exhibit substantial phenotypic variability, but the basis is usually unknown. Mutations in MERTK cause recessive IPD phenotypes associated with the RP38 locus. We have identified a murine genetic modifier of Mertk-associated photoreceptor degeneration, the C57BL/6 (B6) allele of which acts as a suppressor. Photoreceptors degenerate rapidly in Mertk-deficient animals homozygous for the 129P2/Ola (129) modifier allele, whereas animals heterozygous for B6 and 129 modifier alleles exhibit an unusual intermixing of degenerating and preserved retinal regions, with females more severely affected than males. Mertk-deficient mice homozygous for the B6 modifier allele display degeneration only in the far periphery, even at 8 months of age, and have improved retinal function compared to animals homozygous for the 129 allele. We genetically mapped the modifier to an approximately 2-megabase critical interval that includes Tyro3, a paralog of Mertk. Tyro3 expression in the outer retina varies with modifier genotype in a manner characteristic of a cis-acting expression quantitative trait locus (eQTL), with the B6 allele conferring an approximately three-fold higher expression level. Loss of Tyro3 function accelerates the pace of photoreceptor degeneration in Mertk knockout mice, and TYRO3 protein is more abundant in the retinal pigment epithelium (RPE) adjacent to preserved central retinal regions of Mertk knockout mice homozygous for the B6 modifier allele. Endogenous human TYRO3 protein co-localizes with nascent photoreceptor outer segment (POS) phagosomes in a primary RPE cell culture assay, and expression of murine Tyro3 in cultured cells stimulates phagocytic ingestion of POS. Our findings demonstrate that Tyro3 gene dosage modulates Mertk-associated retinal degeneration, provide strong evidence for a direct role for TYRO3 in RPE phagocytosis, and suggest that an eQTL can modify a recessive IPD.
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Adenoviral TYRO3 transduction induced OS phagocytosis in Mertk−/−;Tyro3−/− primary mouse RPE, although to a lesser extent than adenoviral MERTK transduction.
“More recently, it was noted that adenoviral TYRO3 transduction induced OS phagocytosis in Mertk−/−;Tyro3−/− primary mouse RPE, although to a lesser extent than adenoviral MERTK transduction (Vollrath et al., 2015).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Vollrath et al., 2015
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The cell biology of the retinal pigment epithelium
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- Authors
- Vollrath, D., Yasumura, D., Benchorin, G., Matthes, M. T., Feng, W., Nguyen, N. M., Sedano, C. D., Calton, M. A., & LaVail, M. M.
- Affiliations
- Stanford Medicine (US)
- University of California, San Francisco (US)
- Corresponding author
- Vollrath, Douglas
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-12-11
- Volume
- 11
- Issue
- 12
- Pages
- e1005723
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC4687644
- OpenAlex
- W2189808142
- Cited by
- 66
- References
- 61
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 10 · 2023: 10 · 2022: 5 · 2021: 4 · 2020: 8 · 2019: 5 · 2018: 4 · 2017: 9 · 2016: 3
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Foundation Fighting Blindness
- Research to Prevent Blindness (EY002162)
- National Institutes of Health (EY002162, EY001919, EY006842)
- University of California, San Francisco
- National Eye Institute (EY 002162, EY20485, P30EY002162, EY006842, T32EY020485, R01EY001919, F32EY006842, R01EY006842, EY001919)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- Tyro3, MERTK, retinal degeneration, genetic modifiers, gene dosage, expression quantitative trait loci, retinal pigment epithelium, phagocytosis, photoreceptor outer segments, recessive inheritance, photoreceptor degeneration
- MeSH terms
- c-Mer Tyrosine Kinase, Animals, Disease Models, Animal, Humans, Phagocytosis, Photoreceptor Cells, Proto-Oncogene Proteins, Retina, Retinal Degeneration, Mice, Knockout, Receptor Protein-Tyrosine Kinases, Mice, Retinal Pigment Epithelium
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