An ENU-Induced Mutation in theMertkGene (Mertknmf12) Leads to a Slow Form of Retinal Degeneration

Maddox, Dennis M.; Hicks, Wanda L.; Vollrath, Douglas; LaVail, Matthew M.; Naggert, Jürgen Κ.; Nishina, Patsy M.

doi:10.1167/iovs.10-7077

Cited by 15 publications

(25 citation statements)

References 34 publications

(22 reference statements)

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“…Our findings are consistent with the slow peripheral retinal degeneration observed in mice with a Mertk missense mutation generated by ENU mutagenesis on a B6 background [ 35 ], and indicate that a widely available line of Mertk knockout mice is hypomorphic for Tyro3 due to reduced expression from a tightly linked Tyro3 129 allele. Thus, both TYRO3 and MERTK likely function to maintain retinal homeostasis in mice by enabling RPE phagocytosis of POS tips, and the conclusion that MERTK plays a predominant role in the process [ 27 ] should be revised.…”

Section: Discussionsupporting

confidence: 88%

Tyro3 Modulates Mertk-Associated Retinal Degeneration

et al. 2015

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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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Section: Discussionsupporting

confidence: 88%

Tyro3 Modulates Mertk-Associated Retinal Degeneration

et al. 2015

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“…Both strains were mapped to Chr. 12 in F2 intercrosses 26,27 and each allele was backcrossed to C57BL/6J for at least ten generations to eliminate unlinked and distantly linked ENU-induced mutations as potential genetic confounds. A positive allelism test between Nemf R86S and Nemf R487G confirmed that the ENU-induced mutations were disease-causing and were not the result of an unknown, but tightly-linked alternate ENU mutation.…”

Section: Methodsmentioning

confidence: 99%

“…12: 65486719-70085250 bp, GRCm38) and the only exonic variant detected among 15 candidate genes analyzed was in the Nemf gene. The B6J- Nemf R487G line (JAX Stock #18870) was derived from an independent ENU mutagenesis screen for eye phenotypes in a C57BL/6J background, also at The Jackson Laboratory 27 . Crossing heterozygous animals from each ENU allele produced affected offspring in an allelism test suggesting the two mutations were in the same gene.…”

Section: Methodsmentioning

confidence: 99%

NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease

et al. 2020

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A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway—Ribosome-associated Quality Control (RQC)—by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF’s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

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“…Compared with Mertk and Tyro3, Axl was the most consistently and strongly induced TAM receptor in macrophages and epithelial cells during primary viral infection, fungal asthma, and viral exacerbation of fungal asthma. Although several individual and combination TAM receptor gene-targeted mice strains are available, all of these adult mice exhibit major immune anomalies that precluded their use in the models used herein (15, 45, 46). Instead, we used mAbs directed against either Axl (42) or Mertk (47) to address the endogenous role of individual TAM receptors in WT mice.…”

Section: Discussionmentioning

confidence: 99%

Axl Receptor Blockade Ameliorates Pulmonary Pathology Resulting from Primary Viral Infection and Viral Exacerbation of Asthma

Shibata

Habiel

Coelho

et al. 2014

The Journal of Immunology

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Viruses utilize Tyro3, Axl, and Mertk (TAM) receptor tyrosine kinases to infect and modulate the immune properties of various cell types leading us to investigate whether TAM receptor activation impacted primary viral infection and viral exacerbation of asthma in experimental models. In these lung-specific models, we observed that Axl was the most abundantly induced TAM receptor protein. During primary respiratory syncytial virus (RSV) infection, anti-Axl mAb treatment significantly increased the number of IFN-γ-producing T cells and NK cells, and significantly suppressed RSV replication and whole lung levels of IL-4 and IL-13. Intrapulmonary H1N1 infection induced lethal pulmonary inflammation but anti-Axl mAb treatment of infected mice significantly increased the number of IFN-β-producing macrophages and dendritic cells, and significantly suppressed neutrophil infiltration. Consequently, the lethal effect of H1N1 infection in this model was significantly reduced in the mAb-treated group compared with the IgG control-treated group. Targeting Axl also inhibited airway hyperresponsiveness, IL-4 and IL-13 production, and goblet cell metaplasia in an Aspergillus fumigatus-induced asthma model. Finally, infection of mice with RSV during fungal asthma significantly exacerbated airway inflammation, goblet cell metaplasia, and airway remodeling but all of these features in this viral exacerbation model were ameliorated by anti-Axl mAb treatment. Together, these results demonstrate that Axl modulates the pulmonary immune response during viral and/or allergic pathology, and also suggest that targeting this TAM receptor might provide a novel therapeutic approach in these infectious diseases.

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An ENU-Induced Mutation in theMertkGene (Mertk^nmf12) Leads to a Slow Form of Retinal Degeneration

Cited by 15 publications

References 34 publications

Tyro3 Modulates Mertk-Associated Retinal Degeneration

Tyro3 Modulates Mertk-Associated Retinal Degeneration

NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease

Axl Receptor Blockade Ameliorates Pulmonary Pathology Resulting from Primary Viral Infection and Viral Exacerbation of Asthma

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