International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 18 - ANALYSIS OF OVERLAPPING FUNCTIONS OF SMAD2 AND SMAD3 USING CHEMICALLY-INDUCED GERMLINE MOUSE SMAD2 MUTATIONS

Vivian J 1, Magnuson T 2

1 Institute of Maternal-Fetal Biology, University of Kansas Medical Center, Kansas City, KS, United States, 2 Department of Genetics, University of North Carolina, Chapel Hill, NC, United States

Smad2 and Smad3 are closely related intracellular transcriptional regulators and mediate TGF-beta, nodal, and activin signaling. Mice lacking Smad2 die at perigastrulation stages, whereas mice lacking Smad3 develop colorectal carcinoma.  Combination of mutations in these genes will provide further understanding of the overlapping functions of these factors in vivo.  We are exploring this overlap in function using two germline Smad2 mutations identified in a gene-directed screen of chemically mutagenized mouse embryonic stem cells.  One Smad2 mutation used in this study has previously been shown to be hypomorphic in function.  A variety of phenotypes were observed when this hypomorphic allele of Smad2 is combined with a null allele of Smad3.  The embryos lack a well-defined forebrain, and have left-right patterning defects.  More severely affected embryos lack a portion of the anterior notochord.  These phenotypes were not observed in either Smad2 or Smad3 mutant background alone, suggesting these factors share function in forebrain development, left-right patterning, and formation of the notochord.  The molecular deficits underlying these phenotypes are currently being explored.  We are also examining a new mutation in Smad2, which is viable in the homozygous state.  This allele harbors a point mutation within a region of Smad2 altered in some human hepatocellular carcinomas. We are exploring whether this mutation will provide insight into Smad2 function in tumor progression by combining this mutation with the null allele of Smad3.

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