Tyro3 Modulates Mertk-Associated Retinal Degeneration

Abstract

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.

Receptor MER Tyrosine Kinase Proto-oncogene (MERTK) Is Not Required for Transfer of Bis-retinoids to the Retinal Pigmented Epithelium

“…In macrophages, tyrosine phosphorylation of Mertk in response to apoptotic cells is attenuated by deletion of the Axl and Tyro3 genes, suggesting that these receptors interact, possibly by forming heterodimers (36). Indeed, Tyro3 was identified as a murine genetic suppressor of Mertk-associated photoreceptor degeneration (37).…”

Assessment of Murine Retinal Function by Electroretinography

“…Note: Statistical analysis of a-wave and b-wave amplitude shown is based on data in Vollrath et al (2015), and may not be appropriate for every data set. …”

“…The ERG is a useful tool for measuring retinal responses in mice due to its high level of sensitivity and noninvasive nature, and can be utilized to assess eye disease and retinal degeneration (Duncan et al, 2003; Phillips et al ., 2010; Zhao et al, 2011; Vollrath et al , 2015). In mouse genetic retinal disease models, ERGs can be used to assess retinal degeneration at multiple time points as the disease progresses (Duncan et al., 2003).…”

Peripheral Blood Mononuclear Cell Secretome for Tissue Repair

“…Defects during these physiological processes cause autoimmune diseases or macular degeneration in the eye [43]. Apoptotic lymphocytes are known to play important roles in the pathophysiology of several chronic inflammatory diseases and are elevated following implantation of left-ventricular assistance devices [44] or heart transplantation [45] and during hemodialysis [46,47], sepsis [48][49][50], COPD, and asthma (reviewed in [51]).…”