Investigation of proto-oncogene function in normal development as opposed to tumorigenesis is now possible by using embryonic stem cell technology to examine the results of mutation in specific oncogenes in a physiological context. Gene targeting in embryonic stem cells has been used to generate mice with a mutation in the c-myc proto-oncogene. This mutation is lethal in the homozygous state by 10.5 days of gestation. Of the 28 homozygous embryos analyzed, 86% showed evidence of cardiac failure. Since the c-myc phenotype has other abnormalities in addition to cardiac malfunction, the first goal of this proposal is to determine whether the cardiac defect is due to the c-myc mutation in cells destined to form the heart. To this end, rescue of c-myc mutant mice will be attempted with a c-myc transgene which is expressed in cardiac tissue only. Development can be viewed as a balance between proliferation and differentiation, and in vivo evidence suggests a role for c-myc in that relationship. The failure of cardiac development may be due to a lack of division of myocardial cell precursors, failure to differentiate into contractile tissue, or an inability to respond to growth factors associated with cardiac development. Homozygous c-myc mutant embryonic stem cell lines have been generated and will be used to analyze the differentiation capacity of c-myc deficient cells in tissue culture, in teratocarcinomas, and in chimeric embryos. In addition, other potentially hypomorphic alleles will be generated. These will be useful to dissect the relationship between c-myc protein lack of function and phenotype and between myc family members. Specifically homologous recombination in ES cells will be used to replace the c-myc coding sequence with N-myc coding sequences. Comparison with the c-myc null phenotype will allow us to test the ability of N-myc to substitute for c-myc function in a physiological context. In addition, a mutation which allows only the smaller of the two myc translation products to be made will be generated by the hit and run method.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Baylor College of Medicine
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