title: An ENU-induced mutation in the Mertk gene (Mertknmf12) leads to a slow form of retinal degeneration.
abstract: OBJECTIVE
  To determine the basis and to characterize the phenotype of a chemically induced mutation in a mouse model of retinal degeneration.
  
  
  METHODS
  Screening by indirect ophthalmoscopy identified a line of N-ethyl-N-nitrosourea (ENU) mutagenized mice demonstrating retinal patches. Longitudinal studies of retinal histologic sections showed photoreceptors in the peripheral retina undergoing slow, progressive degeneration. The mutation was named neuroscience mutagenesis facility 12 (nmf12), and mapping localized the critical region to Chromosome 2.
  
  
  RESULTS
  Sequencing of nmf12 DNA revealed a point mutation in the c-mer tyrosine kinase gene, designated Mertk(nmf12). We detected elevated levels of tumor necrosis factor (Tnf, previously Tnfa) in retinas of Mertk(nmf12) homozygotes relative to wild-type controls and investigated whether the increase of TNF, an inflammatory cytokine produced by macrophages/monocytes that signals intracellularly to cause necrosis or apoptosis, could underlie the retinal degeneration observed in Mertk(nmf12) homozygotes. Mertk(nmf12) homozygous mice were mated to mice lacking the entire Tnf gene and partial coding sequences of the Lta (Tnfb) and Ltb (Tnfc) genes.(2) B6.129P2-Ltb/Tnf/Lta(tm1Dvk)/J homozygotes did not exhibit a retinal degeneration phenotype and will, hereafter, be referred to as Tnfabc(-/-) mice. Surprisingly, mice homozygous for both the Mertk(nmf12) and the Ltb/Tnf/Lta(tm1Dvk) allele (Tnfabc(-/-)) demonstrated an increase in the rate of retinal degeneration.
  
  
  CONCLUSIONS
  These findings illustrate that a mutation in the Mertk gene leads to a significantly slower progressive retinal degeneration compared with other alleles of Mertk. These results demonstrate that TNF family members play a role in protecting photoreceptors of Mertk(nmf12) homozygotes from cell death.
authors: Nishina Laboratory, The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors: Dennis M
authors: DM
authors: Maddox
authors: Wanda L
authors: WL
authors: Hicks
authors: Douglas
authors: D
authors: Vollrath
authors: Matthew M
authors: MM
authors: LaVail
authors: Jürgen K
authors: JK
authors: Naggert
authors: Patsy M
authors: PM
authors: Nishina
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004596:Electroretinography; D005038:Ethylnitrosourea / Q000633:toxicity*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000187:drug effects*; D009887:Ophthalmoscopy; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000076202:c-Mer Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D005038:Ethylnitrosourea