International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


J Vivian
University of North Carolina-Chapel Hill

Chen Y, Magnuson T
University of North Carolina

An efficient means of creating an allelic series of subtle mutations in the mouse, non-null mutations in particular, would greatly aid the analysis of complex gene function. Smad2 is an intracellular transcriptional regulator activated by TGFb?? nodal, and activin signaling. The early lethality of targeted Smad2 mutations, along with the various protein interactions and signaling pathways mediated by this factor suggested that Smad2 would be excellent an candidate for the development of an allelic series of subtle mutations. Our laboratory has recently extended a chemical mutagenesis strategy in mouse embryonic stem cells to identify ENU-induced mutations in non-selectable loci. Using this methodology we have identified several subtle mutations within the coding region of Smad2. In vivo analysis of a germline mutation obtained in this screen identifies this mutation to be hypomorphic in character, allowing for functional analysis of Smad2 in later embryonic stages than allowed by the available targeted alleles. A variety of defects are observed in these Smad2 mutants by E8.5, including defects in the formation of anterior neurectoderm, dorsal aorta, foregut, heart, and anterior notochord. Our work demonstrates that a large number of useful mutations in nonselectable genes can be readily identified by combining ENU mutagenesis with high throughput mutation detection. The further analysis of this as well as other subtle Smad2 mutations will allow for a better understanding of the roles of this factor in various biological processes.

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