Effects of tyrosine hydroxylase mutants on locomotor activity in Drosophila: a study in functional genomics.
The brain of the adult fruit fly, Drosophila melanogaster, contains tyrosine hydroxylase, the rate-limiting enzyme required for catecholamine biosynthesis, as well as dopa decarboxylase. Catecholamines, principally dopamine, are also present. We have previously shown that pharmacological inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine results in a dose-related inhibition of locomotor activity in adult organisms. Similar results were found with reserpine, a well-known inhibitor of catecholamine uptake into storage granules. The drug-induced inhibition could be prevented in each case by the concomitant administration of L-dopa. The single-copy gene coding for tyrosine hydroxylase in Drosophila is pale (ple). Both null and temperature-sensitive loss of function mutant alleles of ple are recessive embryonic lethals. Heterozygous null mutant flies have normal locomotor activity demonstrating that only a single dose of the wild type form of ple is required to support normal function. Both hemizygous and homozygous temperature-sensitive ple mutants (ple(ts1)) also show normal locomotor activity at the permissive temperature for this mutant allele (18 degrees C), which progressively declines as the temperature is increased to its restrictive level (29 degrees C). These abnormal locomotor effects are reversible by L-dopa. Thus the effects on locomotor activity resulting from the pharmacological inhibition of catecholamine synthesis or storage are the same as those resulting from lack of tyrosine hydroxylase expression. These findings indicate that brain catecholamine loss decreases locomotor activity in the fly, as it does in mammals, and demonstrate the ability of functional genomic studies to mimic that of pharmacological inhibition of enzyme function or other similar processes.
Pendleton
Robert G
RG
Department of Biology, Temple University, Philadelphia, Pennsylvania 19122, USA. rgp@mymailstation.com
Rasheed
Aseel
A
Sardina
Thomas
T
Tully
Tim
T
Hillman
Ralph
R
D000483:Alleles; D000818:Animals; D001921:Brain / Q000378:metabolism; D004331:Drosophila melanogaster; D015971:Gene Expression Regulation, Enzymologic; D008124:Locomotion / Q000235:genetics*; D026161:MADS Domain Proteins; D009154:Mutation / Q000235:genetics*; D010940:Plant Proteins / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*
D026161:MADS Domain Proteins; C079380:PLE protein, Antirrhinum majus; D010940:Plant Proteins; D014446:Tyrosine 3-Monooxygenase