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Background   Jeff  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.    Results  Phospho-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.    Conclusion  Overall, 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.

Regulation of TGF-β signalling by Fbxo11, the gene mutated in the Jeff otitis media mouse mutant