A mutation (dosach) in Drosophila which affects aster formation and nuclear migration during cleavage.

Here we describe a new mutant, dosach (dos), in Drosophila melanogaster. In the mutant, centrosomes divide and initiate spindle formation similar to that seen in wild-type embryos. Nevertheless, mutant embryos form cleavage spindles that lack visible asters and display abnormal morphology, including mono- and tri-polar spindles, spindle chains and incorrect alignment. Irregular nuclear migration is also observed in mutant embryos, and this may suggest that astral microtubules are important for spindle spacing during cleavage and also in maintaining the integrity of the mitotic apparatus. Confocal microscopy has been used to correlate organization of microtubules, centrosomal proteins and chromosomes in wild-type and dosach (dos) embryos.

Mutations in supernova, indicate that this gene is required for the division of germ line cells in Drosophila.

Mutations in supernova, previously shown to uncouple chromosome replication from segregation during cleavage in Drosophila embryos, also sanctions extra divisions of cystoblasts and spermatoblasts. This leads either to the formation of egg chambers which contain more than fifteen nurse cells or testes which have an excess of spermatocytes. In maturing egg chambers two potential oocytes may be specified in which case they are often ectopically located and connected with surrounding nurse cells by four ring canals. However, a typical oocyte nucleus is not always present and these chambers usually become necrotic and degenerate. The nurse cells are of variable size, but are still interconnected by a system of ring canals. They all possess a polyploid nucleus. Sequestering of maternal mRNA's from the nurse cells into the potential oocyte(s) takes place but there is no localization of this maternal information within the oocyte probably because of defective microtubule assembly. Many spermatocytes fail to complete meiosis so that bundles of spermatids are reduced in size and the males have reduced fertility. It is proposed that this gene is indirectly involved in regulating the timing of mitotic divisions in both cystoblasts and spermatoblasts through its interference with microtubule assembly which is consistent with its role during embryogenesis.

Supernova (spno), a new maternal mutant producing variable-sized cleavage nuclei in Drosophila.

This paper describes a new recessive maternal lethal which disrupts normal nuclear division and migration during cleavage in Drosophila. We have named this gene locus supernova. Deletion mapping and in situ hybridization have located this gene to 88 F9/89 A1 on the polytene chromosome map. The terminal mutant phenotype is characterized by the presence of many variable-sized nuclei scattered throughout the cytoplasm of the unhatched egg. Following fertilization, the initial cleavage divisions appear delayed and are often accompanied by the formation of ring-like association of chromosomes and/or chromosome bridges. Although the polymerization of tubulin into spindles occurs during the initial cleavage divisions, there appears to be both a spatial and temporal uncoupling of DNA replication from the formation and proper functioning of spindles. Eventually no functional spindles are formed, but nuclei continue to increase in size and number with increasing age of the embryo following fertilization.

Somatic mutation induced by heliotrine in Drosophila.

The pyrrolizidine alkaloid heliotrine has been shown to be a powerful mutagen in Drosophila. This report has evaluated the teratogenicity of heliotrine in this organism. The alkaloid was fed to larvae and its teratogenic effects measured in various developmental stages of the insect. The pupal stage is predominantly affected. The main consequences of treatment were failed eclosions at higher alkaloid concentrations (10(-4) M), while lower concentrations (10(-5) M) permitted the eclosion of adults, but these showed abdominal abnormalities ranging from severe distortions to reduced numbers of tergite bristles. mei-9 strains of Drosophila were more sensitive to the production of somatic chromosomal changes as well as the teratogenic effects of the alkaloid. These strains also showed reduced numbers of cells in histoblast nests of 6-hour-old prepupae. It is suggested that reduced numbers of histoblast cells in prepupae may be a consequence of genetic damage and this in turn leads to the abdominal distortions and reduced bristle numbers observed.

Dependence proneness, a key target for alcoholism research.

Many alcoholics appear to be especially susceptible to developing tolerance to and physical dependence on alcohol. Elucidation of a biochemical abnormality associated with this special proneness could lead to advances in both diagnosis and treatment of alcoholism.

Steroidal androgen biosynthesis inhibitors.

PIP: 23,17beta-acylaminoandrost-4-en-3-ones and 3 previously known nonsteroids were synthesized and screened as inhibitors of 17,20-lyase, a step in androgen synthesis from progesterone or OH-progesterone. The screening involved measuring side chain cleavage (carbon-14-acetate release) from 21-carbon-14-17alpha-OH-progesterone by rat testis microsomes. The amide, urea, guanidino and carbamate derivatives were also tested by conversion of cholesterol to pregnenolone by a bovine corpora lutea acetone powder, by conversion of corticosterone to 18-OH-corticosterone by crude adrenal mitochondria, and by feeding to male rats to check effect on adrenal weight and testis testosterone level. More than 80% inhibition was achieved with androst-4-en-3-ones having the C-17beta carbamate, formamido, acetamido and ureido groups. These compounds did not inhibit OH-corticosterone synthesis. 6-alpha methylation inhibited the lyase 50-70%. 1 compound 17-beta-ureidoandrost-1,4-dien-3-one was fed to male rats for 6 weeks at 500 mg per kg; it reduced testis testosterone but not adrenal weight. Selective inhibition of androgen synthesis would be useful for treating benign prostate hypertrophy, hirsutism, acne and androgen dependent tumors.^ieng