Effects of the lethal yellow (A*) mutation in mouse aggregation chimeras

The A allele is a recessive lethal mutation at the mouse agouti locus, which results in embryonic death around the time of implantation. In the heterozygous state, A produces several dominant pleiotropic effects, including an increase in weight gain and body length, a susceptibility to hepatic, pulmonary and mammary tumors, and a suppression of the agouti phenotype, which results in a yellow coat color. To investigate the cellular action of A with regard to its effects upon embryonic viability and adult-onset obesity, we generated a series of aggregation chimeras using embryos that differ in their agouti locus genotype. Embryos derived from A/axA/a matings were aggregated with those derived from A/Ax A/A matings, and genotypic identification of the resultant chimeras was accomplished using a molecular probe at the Emv-15 locus that distinguishes among the three different alleles, A, A, and a. Among 50 chimeras, 25 analyzed as liveborns and 25 as 9.5 day embryos, 29 were a/a*-+A/A and 21 were A/a+->A/A. The absence of A/A<r+A/A chimeras demonstrates that A/A cells cannot be rescued in a chimeric environment, and the relative deficiency of A/a*-+A/A chimeras suggests that, under certain conditions, A heterozygosity may partially affect cell viability or proliferation. In the 25 liveborn chimeras, Aja*^AJA animals became obese as adults and a/a+-*A/A animals did not. There was no correlation between genotypic proportions and rate of weight gain, which shows that, with regard to its effects on weight gain, A heterozygosity is cell non-autonomous.