Two Pathways for GM2(NeuGc) Expression in Mice: Genetic Analysis

We have reported that WHT/Ht mice express neither GM2(NeuGc) nor GM1(NeuGc) in the liver or erythrocytes due to a defect on the Ggm-2 gene, which was demonstrated to control the activity of UDP-GalNAc:GM3(NeuGc) N-acetylgalactosaminyltransferase in mouse liver, and, in addition, WHT/Ht mice do not express a detectable amount of GM2(NeuGc) but do express GM1(NeuGc) in tissues other than the liver and erythrocytes, such as the spleen, thymus, heart, lung, kidney, and testis [Nakamura et al. (1988) J. Biochem. 103,201–208]. In order to determine whether the phenotype of WHT/Ht mice exhibiting an undetectable amount of GM2(NeuGc) in these tissues is genetically controlled or not, we analyzed the expression of gangliosides in the progeny obtained on backcross mating between (BALB/c×WHT/Ht)F1 and WHT/Ht mice, and in a GM2(NeuGc) congenic mouse, WHT.C. Concerning the expression of GM2(NeuGc) in the liver, lung, and kidney, 102 backcross mice could be segregated into two types. One type expressed a detectable amount of GM2(NeuGc) in the liver, lung, and kidney, and the other type did not. The ratio of the numbers of mice exhibiting these two types was 42 : 60, indicating that the two phenotypes were genetically determined by the involvement of a single autosomal gene. Recombination as to GM2(Neu-Gc) expression in the liver, lung, and kidney was not detected among the 102 backcross mice. Analysis of the GM2(NeuGc) congenic mouse indicated that a detectable amount of GM2(NeuGc) was expressed in the liver, erythrocytes, lung, kidney, heart, spleen, and small intestine. The GM2(NeuGc) congenic mouse is considered to carry all the chromosomes of the WHT/Ht mouse, except for an about 15 centimorgan long chromosome segment derived from the BALB/c mouse and responsible for the positive expression of GM2(NeuGc) in the liver. These results, therefore, indicate that Ggm-2 itself, or a gene or genes closely linked to it, is responsible for the expression of a detectable amount of GM2(NeuGc) in tissues other than the liver and erythrocytes. On the basis of these results, we suggest that there are at least two pathways for the biosynthesis of GM2(NeuGc), and that WHT/Ht mice can biosynthesize GM2(NeuGc) and GMl(NeuGc), even if GM2(NeuGc) is not detected by the method we used, under the involvement of autosomal genes independent of Ggm-2 in the tissues other than the liver and erythrocytes.