International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


L Matesic
National Cancer Institute

2) Haines D, 1) Copeland N, 1) Jenkins N
1) National Cancer Institute, 2) SAIC Frederick

Human autoimmune diseases are complex and the identification of a single-gene mouse model may provide unique insights into the etiology of diseases such as SLE, IBD, and Crohn’s disease and potentially uncover novel targets for anti-inflammatory drugs.  Mice homozygous for the itchy (itch) mutation develop an autoimmune-like disease characterized by generalized systemic inflammation and die of hypoxia caused by chronic pulmonary inflammation with alveolar proteinosis at 6-8 months of age.  IgG deposits can be detected in the glomeruli and anti-nuclear antibodies in the sera as early as 10 weeks of age.  This autoimmune-like disease results from a loss of function mutation in a HECT E3 ubiquitin protein ligase.  Phylogentic analysis suggests that Itch is the mouse ortholog of Drosophila suppressor of deltex, Su(dx).  Su(dx) functions in Notch signaling, as loss of function Su(dx ) mutations enhance gain of function mutations in Notch. Further, in vitro studies show that Itch is capable of attenuating Notch signaling by ubiquitinating mouse Notch1.  In order to assess the role of Itch in Notch signaling in vivo, we bred itch mice with mice carrying an activated Notch1 transgene.  Interestingly, itch mice that carry this transgene are significantly smaller than their littermates and die at 8-10 weeks of age.  They also have the same autoimmune disease seen in itch; however, the lesions are more severe and develop much sooner.  Itch thus enhances a gain of function of Notch1 allele and suggests that Itch and Notch1 may play pivotal roles in the etiology of autoimmune disease.

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