Abstract
BackgroundJeff is a dominant mouse mutant displaying chronic otitis media. The gene underlying Jeff is Fbxo11, a member of the large F-box family, which are specificity factors for the SCF E3 ubiquitin ligase complex. Jeff homozygotes die shortly after birth displaying a number of developmental abnormalities including cleft palate and eyes open at birth. TGF-β signalling is involved in a number of epithelial developmental processes and we have investigated the impact of the Jeff mutation on the expression of this pathway.ResultsPhospho-Smad2 (pSmad2) is significantly upregulated in epithelia of Jeff homozygotes. Moreover, there was a significant increase in nuclear localization of pSmad2 in contrast to wild type. Mice heterozygous for both Jeff and Smad2 mutations recapitulate many of the features of the Jeff homozygous phenotype. However, tissue immunoprecipitations failed to detect any interaction between Fbxo11 and Smad2. Fbxo11 is known to neddylate p53, a co-factor of pSmad2, but we did not find any evidence of genetic interactions between Jeff and p53 mutants. Nevertheless, p53 levels are substantially reduced in Jeff mice suggesting that Fbxo11 plays a role in stabilizing p53.ConclusionOverall, our findings support a model whereby Fbxo11, possibly via stabilization of p53, is required to limit the accumulation of pSmad2 in the nucleus of epithelial cells of palatal shelves, eyelids and airways of the lungs. The finding that Fbxo11 impacts upon TGF-β signalling has important implications for our understanding of the underlying disease mechanisms of middle ear inflammatory disease.
Highlights
Jeff is a dominant mouse mutant displaying chronic otitis media
Given the findings of a palatal and eyes-open at birth (EOB) phenotype in Jeff mice and the role of transforming growth factor b (TGF-b) signalling in these processes, we have focused our studies on salient members of the TGF-b family signalling pathway and demonstrated that pSmad2 is upregulated in the epithelia of Jeff homozygotes
Palatal expression in Jeff mutants Jeff homozygote palatal shelves start to grow and lift on time, but they fail to fuse at the right developmental stage (Figure 1a) and homozygote mice are born with cleft palate (Figure 1b)
Summary
Jeff is a dominant mouse mutant displaying chronic otitis media. The gene underlying Jeff is Fbxo, a member of the large F-box family, which are specificity factors for the SCF E3 ubiquitin ligase complex. From a deafness screen as part of the MRC Harwell mouse mutagenesis programme [6] we have identified two novel dominant mutants, Jeff and Junbo, which develop a conductive deafness due to a chronic suppurative OM [7,8,9]. Both these mutants represent the first models for chronic forms of middle ear inflammatory disease in humans, and both of these mutants have been cloned [8,9]
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