The human gene that codes for the protein ␣-synuclein has been transferred into the Drosophila melanogaster genome. The transgenic flies recapitulate some of the essential features of Parkinson's disease. These include the degeneration of certain dopaminergic neurons in the brain accompanied by the appearance of age-dependent abnormalities in locomotor activity. In the present study, we tested the locomotor response of these transgenic flies to prototypes of the major classes of drugs currently used to treat this disorder. A time course study was first conducted to determine when impaired locomotor activity appeared relative to normal "wild-type" flies. A climbing or negative geotaxis assay measuring the ability of the organisms to climb up the walls of a plastic vial was used. Based on the results obtained, normal and transgenic flies were treated with each of the drugs in their food for 13 days and then assayed. The activity of transgenic flies treated with L-DOPA was restored to normal. Similarly, the dopamine agonists pergolide, bromocriptine, and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-
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.
In Drosqphila melanogaster embryos cuticle formation occurs between 12 and 16 hours of development at 25°C. The formation of the cuticulin and the protein epicuticular layers is simultaneous in the hypoderm, the tracheoblasts, and the fore-and hindgut cells. The cuticulin forms as a dual lamina, aggregating from granules secreted by the hypodermal cells. This is followed by the formation of a granular protein epicuticle and finally by the secretion of a mixed fibrous and granular endocuticle.All secretory cells are relatively simple in their ultrastructure. The secretory process is a membrane phenomenon, occurring at the tips of hypodermal microvillae on cells at the surface of the embryo and on those hypodermal cells lining the Iumen of the fore-and hindgut. It also occurs along the entire surface of the tracheoblast lumen as well as on the outer surface of those cells which form exoskeletal chitinous setae. The process involves a specialization of the plasma membrane with the formation of secretory granules intracellularly beneath the membrane and the extrusion of these granules through the membrane to the outside where final cuticle formation occurs.Reviews of the molecular structure (Rudall, '63), development (Locke, '64) and chemical composition (Hackman, '64) of the insect cuticle have recently been published. In addition, Locke ('66, '69) has published more detailed accounts of the ultrastructure of the hypodermal epicuticle secreting cells of Calpodes ethlius larvae. These latter reports are the first extensive investigations of the structure of the cuticle secreting cells. The description which emerges from this work of Locke is that of an intricate, highly organized cellular machinery which is designed for and functions in the formation of the chitinprotein complex which makes up the insect cuticle.We know very little concerning the cellular mechanisms involved in the production of the cuticle in Drosophila. A brief description of the process of cuticle formation in the prepupal-pupal stages in the Diptera Cyclorrhapha can be found in a report by Whitten ('57). The formation of the first larval instar cuticle during the embryonic stages was described by Poulson ('50) at the level of the light microscope. According to this report cuticle formation begins in the twelfth embryonic hour and proceeds rapidly, resulting in a thin flexible envelope. Poulson was unable J. MORPH., 131: 383-396.to describe any layering in this larval structure when it formed during embryogenesis.The study described here was begun, as an investigation of the sequence of events which take place during the formation of the larval cuticle of Drosophila. Since this is a study of the initial deposition of cuticle by embryonic cells, the description defines and delineates a specific primary function of one cell type. These cells are involved only in cuticle secretion and are not involved in the resorption of old cuticle. This report will describe and compare the process of cuticle formation in the hypodermal cells secreting s...
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