[Architecture of the X chromosome, expression of LIM kinase 1, and recombination in the agnostic mutants of Drosophila: a model of human Williams syndrome]. / Osobennosti arkhitektury X-khromosomy, ékspressii LIM kinazy 1 i rekombinatsii u mutantov drozofily lokusa agnostic: model' sindroma uil'iamsa cheloveka.

As the Human Genome and Drosophila Genome Projects were completed, it became clear that functions of human disease-associated genes may be elucidated by studying the phenotypic expression of mutations affecting their structural or functional homologs in Drosophila. Genomic diseases were identified as a new class of human disorders. Their cause is recombination, which takes place at gene-flanking duplicons to generate chromosome aberrations such as deletions, duplications, inversions, and translocations. The resulting imbalance of the dosage of developmentally important genes arises at a frequency of 10(-3) (higher than the mutation rate of individual genes) and leads to syndromes with multiple manifestations, including cognitive defects. Genomic DNA fragments were cloned from the Drosophila melanogaster agnostic locus, whose mutations impair learning ability and memory. As a result, the locus was exactly localized in X-chromosome region 11A containing the LIM kinase 1 (LIMK1) gene (CG1848), which is conserved among many species. Hemizygosity for the LIMK1 gene, which is caused by recombination at neighboring extended repeats, underlies cognitive disorders in human Williams syndrome. LIMK1 is a component of the integrin signaling cascade, which regulates the functions of the actin cytoskeleton, synaptogenesis, and morphogenesis in the developing brain. Immunofluorescence analysis revealed LIMK1 in all subdomains of the central complex and the visual system of Drosophila melanogaster. Like in the human genome, the D. melanogaster region is flanked by numerous repeats, which were detected by molecular genetic methods and analysis of ectopic chromosome pairing. The repeats determined a higher rate of spontaneous and induced recombination. including unequal crossing over, in the agnostic gene region. Hence, the agnostic locus was considered as the first D. melanogaster model suitable for studying the genetic defect associated with Williams syndrome in human.

[Cyclic nucleotide phosphodiesterases in mutant lines of Drosophila melanogaster]. / Izuchenie aktivnosti fosfodiésterazy tsiklicheskikh nukleotidov u mutantnykh linii Drosophila melanogaster.

The activities of general phosphodiesterase and its Ca(2+)-calmodulin-independent from (PDE-1) were studied in strains mutant for the agnostic gene and in the strain Canton S. Enzyme activity was determined in males and homo- and hemizygous females of four strains. It was found that mutation at the agnostic gene resulted in increased PDE-1 activity. This effect appears to depend on the dose of the mutant gene, because it was revealed only in homozygous females. We have substantiated the notion that the agnostic gene controls calmodulin properties by virtue of encoding a calmodulin-inhibiting protein.

Genetic approaches to the study of memory in insects.

This article provides a short summary of studies carried out on mutant Drosophila with defects in learning ability, including our own experimental data on the role of the tryptophan oxygenase gene (this is a key enzyme, and is the first enzyme in the tryptophan-ommochrome metabolic pathway) in the inherited determination of learning ability and memory in the honey bee. A set of allelic mutations was used which inhibit the activity of this enzyme to different extents, resulting in the complete lack of kynurenines or particular levels of kynurenine deficiency in the mutant organisms. The effects of mutations at the snow locus (snow, s, snowlaranja, sla) on the dynamics of memory trace formation after single training sessions were studied in the honey bee and were related to the activity of the enzyme responsible for hydrolysis of cyclic nucleotides (phosphodiesterase). Relationships were found between the level of disruption in the dynamics of memory trace formation and changes in kynurenine content and phosphodiesterase activity.

Mutational analysis and genetic cloning of the agnostic locus, which regulates learning ability in Drosophila.

P-insertion mutations were obtained and localized by in situ methods at the agnostic gene (agn: 1-38.9; 11AB) in Drosophila. All agn mutants showed a wide spectrum of pleiotropic effects: an EMS-induced mutation of the agn-ts398 improved the ability to develop a conditioned defensive response and increased the activity of cAMP metabolic enzymes; spontaneous mutation of agnX1 showed morphological defects of the brain. P-insertion mutations were used to clone the gene; a restriction map of 80 kb in length was determined, and the insertion was localized to a fragment of 9 kb.

[Genetic approaches to the study of memory in insects]. / Geneticheskie podkhody k izucheniiu pamiati u nasekomykh.

The paper presents some experimental data on the structural gene of tryptophanoxygenase and its role in hereditary determination of learning ability and memory in honey bees. Changes in the memory trace formation were shown to depend on the degree of breaks in the kynurenine and phosphodiesterase activity.

[Mutational analysis and genetic cloning of the agnostic locus controlling learning ability in Drosophila]. / Mutatsionnyi analiz i geneticheskoe klonirovanie lokusa agnostic, kontroliruiuschego sposobnost'k obucheniiu, u drozofily.

The ts-mutations of the agnostic gene either increased or decreased the activity of the AC and PDE. A chromosomal deficiency in the 11B region failed to complement with the agnostic behavioral defect like agn P29 and P40, led to an increased proportion of the PDE-1 in total PDE and to the structural defects in the central complex thus indicating that the P insertion is responsible for the mutant agnostic phenotype.

[Phospholipids of the subcellular fractions of brain and liver tissues in rats in total oxygen starvation of the body]. / Fosfolipidy subkletochnykh fraktsii tkanei mozga i pecheni krys pri obshchem kislorodnom golodanii organizma.

The rate of phospholipid turnover in brain subcellular fractions differ from that in the liver tissue. Hypoxia of medium severity (pressure chamber 240 mm Hg) influences neither the content nor the turnover rate of phospholipids in liver subcellular fractions. Meanwhile in brain subcellular fractions, it results in a decreased phospholipid turnover rate. Severe hypoxia (less than 200 mm Hg) leads only to the suppression of the phospholipid turnover rate in the liver, whereas in the brain, it results in the decline of the phospholipid turnover rate as well as in the reduction of phospholipid content. Thus, the well-known concept of the higher brain sensitivity to oxygen deficiency as compared to the liver is exemplified by phospholipid turnover in subcellular fractions.

[Effect of cerebral blood supply disorders on certain aspects of metabolism]. / Vliianie narusheniia krovosnabzheniia golovnogo mozga na nekotorye storony ego metabolizma.

Bilateral ligation of common carotid arteries sharply decreases volume blood flow and oxygen consumption in the cortex, in diencephalon and midbrain whereas inducing no changes in the cerebellum and medulla oblongata. The same is true for intensity of metabolism of both total and separate fractions of phospholipids. This suggests that the changes of phospholipid metabolism in neural tissue depend on the degree of its blood supply disturbance and duration of the ischemia.

[Phospholipid metabolism in the microsomes and cytosol of the brain tissue of normal rats and rats with hypoxic hypoxia]. / Metabolizm fosfolipidov v mikrosomakh i tsitozole tkani golovnogo mozga krys v norme i pri gipoksicheskoi gipoksii.

The content and the intensity of metabolism of various phospholipid groups (phosphatidylcholines, monophosphoinositides, aminophospholipids) was studied in the homogenate, microsomes, and cytozol of the rat brain under normal conditions and in hypoxic hypoxia (240 mm Hg). Phospholipid content per 1 mg of protein was the highest in the microsomes, and the least in the cytozol. However, the total phospholipids of the cytozol had the greatest rate of metabolism of their phosphate groups. Without influencing the phospholipid content, hypoxia depressed the intensity of their metabolism, and this depression proved to be approximately the same in all the tissue preparations under study.