International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


ORAL PRESENTATION

TUESDAY 11 NOVEMBER
14:15 – 14:30 HRS

A DEFECT IN A NOVEL ADAMTS FAMILY MEMBER IS THE CAUSE OF THE BELTED WHITE-SPOTTING MUTATION

Beier DR
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Co-Authors: 1) Rao C, 1) Foernzler D, 2) Loftus S, 1) Liu S, 3) McPherson J, 4) Jungers K, 5) Apte S, 2) Pavan W
Institutions: 1) Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 2) National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; 3) Department of Genetics, Washington University, St. Louis, MO. 4) Dept. of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH

Several features of the pigment defect in belted (bt) mutant mice suggest that it occurs as a result of a defect in melanocyte development that is unique from those described for other classical white-spotting mutations. Using a positional cloning strategy, we have determined that bt is due to a defect in a novel ADAMTS (A Disintegrin-like And Metalloprotease(reprolysin type) with ThromboSpondin type I motif) protein, which is a member of a large family of secreted metelloproteases that are presumed to interact with the extracellular matrix (ECM). A homologous and highly similar protease, Gon-1, has been shown to play a crucial role in cell migration in C. elegans. Our results suggest this function has been conserved in mammalian development. Secreted metalloproteinases could be required for cell migration by virtue of a relatively non-specific modification of the ECM such that it is permissive for cell transit. Alternatively, metalloproteinases may be required for specific processing of secreted guidance factors. Notably, our analysis demonstrates that the bt gene product is not made by melanocytes themselves, but rather by the mesenchyme through which these cells migrate. This result implies that there is a highly coordinated and dynamic pattern of gene expression in the developing embryo that is required for the proper localization of neural-crest-derived cells.


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