Function of the lactate dehydrogenase B gene in mouse erythrocytes: evidence for control by a regulatory gene.

Abstract

Experimental evidence suggests that cells comprising complex multicellular organisms possess qualitatively equivalent ensembles of genes, but the differentiation of these cells requires differential gene expression. According to this hypothesis, differentiation occurs primarily as the result of a patterned activation of certain genes and a repression of others. Developmental control of gene expression can operate at many levels, such as transcription, translation, end product alteration, or combinations of these. It is reasonable to expect that the control processes should themselves be genetically controlled and, as a result, that mutations affecting control should also occur. Evidence for mutations affecting certain levels of control in higher organisms exists in fungi, Drosophila, plants, and mammals.1-3 These examples provide some insight into the mechanisms controlling differential gene expression.In this report we present genetic evidence for a mammalian gene that appears to control the expression of an independent structural gene in a differentiated cell. This gene controls the appearance of the active B subunit, but not the A subunit, of the lactate dehydrogenase (LDH) tetramer in mouse erythrocytes. It has no detectable effect in any other tissue examined. Preliminary evidence has been reported elsewhere.4Lactate dehydrogenase (EC 1.1.1.27) is composed of two electrophoretically distinct subunits, A and B, which associate at random to form five tetrameric isozymes, each with a molecular weight of about 135,000.5 6 The five isozymes are generated by assortment of the A and B subunits into all possible combinations of four.7 Formulas for the five isozymes may be written as follows: BBBB = LDH-1; BBBA = LDH-2; BBAA = LDH-3; BAAA = LDH-4; AAAA = LDH-5. These five forms are the principal lactate dehydrogenase isozymes found ubiquitously in mammals. A high degree of tissue specificity characterizes isozyme patterns. Certain tissues contain more LDH-5 than LDH-1, thus demonstrating that unequal amounts of the A and B subunits are available for tetrameric association. Differential expression of the LDH isozymes has also been shown during specific tissue development.8 The developmental specificity of such tissue indicates that control mechanisms exist for regulating the relative amounts of synthesis of the A and B subunits of LDH.In the present study two lactate dehydrogenase phenotypes were observed in mouse erythrocytes but not in other tissues. In one phenotype, LDH B subunits were expressed, while in the second, LDH B subunits were absent. This phenotypic difference was inherited according to expectations of two alleles at an autosomal locus. The allele that specifies the formation of LDH B subunits is dominant to that which is associated with the absence of these subunits. 574

Polymorphism of lactate dehydrogenase B subunit in rat erythrocytes

“…It seems that the amount of the B subunit in the rodent erythrocytes is controlled by a regulatory locus (Ldr-1) because similar results were found by Shows & Ruddle (1968) in the mouse red blood cells. Recently, another B subunit controlling locus (Ldr-2) was found in the early postnatal mouse liver (Khlebodarova & Serov, 1980).…”

Protein Polymorphism and Genic Heterozygosity in Two European Subspecies of the House Mouse

“…Lactate dehydrogenase regulator locus ( erythrocytes). The two alleles, Ldr-P and Ldr-l", first detected at this locus by Shows and Ruddle (1968a) , are segregating in all six populations sampled. The (Table 3).…”

Genetics of Human-Mouse Somatic Cell Hybrids: Linkage of Human Genes for Lactate Dehydrogenase- A and Esterase-A 4

“…14 Human enzyme phenotypes that differed in electrophoretic mobility or expression from mouse homologous enzymes were tested in hybrids. The enzyme phenotypes were lactate dehydrogenase-A and B (LDH) (18), esterase-A4 (Es-A4) (19), glucose-6-phosphate dehydrogenase (G6PD) (20), (18). A Tris-citrate buffer system was used to separate MDH, ME, PGM, PHI, and AK (21).…”