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PubMed1993

Functional analysis of the mouse homeobox gene HoxB9 in Drosophila development.

Mammalian genomes contain clusters of homeobox genes (Hox-C, HOX-C) which are structurally similar to the homeotic genes of the Drosophila HOM complex. One method for assessing the functional similarity of particular Drosophila HOM and mammalian Hox genes is to test the ability of Hox genes to induce homeotic phenotypes when expressed in developing Drosophila. Here we describe such functional tests using mouse HoxB9 (formerly Hox-2.5), whose closest structural relative in Drosophila is Abdominal-B. When expressed from a heat shock promoter, HoxB9 induces transformations of head towards more posterior identities in Drosophila larvae and adults. These transformations share some similarities with the phenotypic effects produced by ectopically expressed Abdominal-B, but are also similar to the transformations induced by Antennapedia and mouse HoxB6 (Hox-2.2), suggesting that HoxB9 specifies a positional identity that is intermediate between Antennapedia and Abdominal-B.

Amino Acid Sequence↗
PubMed1994

Synaptogenesis in Drosophila: coupling genetics and electrophysiology.

Drosophila is one of the most fully described eukaryotic organisms and, as a system, offers the most advanced genetic and molecular techniques. In particular, Drosophila embryonic development has been subject to intensive genetic and molecular examination. Drosophila is also one of the few genetically malleable organisms to permit electrophysiological investigation and so allow detailed physiological characterization of specific molecular lesions. These two fields, the developmental and electrophysiological, are being coupled for the first time to examine a key aspect of neural development, synaptogenesis. Here, I describe synaptogenesis in the Drosophila embryo at the identified neuromuscular junction. I focus particular attention on the use of known genetic mutations to dissect the mechanisms of synapse formation. This simple, well-characterized synapse is already proving valuable in describing the defects of mutations in genes essential for synaptic development and function. In the long term, this system will allow us to systematically mutate the Drosophila genome to identify and describe the genetic and molecular pathways directing the construction of a synapse.

Animals↗
PubMed2004

Hyperactive spruce budworm antifreeze protein expression in transgenic Drosophila does not confer cold shock tolerance.

Drosophila melanogaster, a freeze intolerant and cold shock sensitive insect, was transformed with the hyperactive insect antifreeze protein gene (AFP) from the spruce budworm, Choristoneura fumiferana. Transformation P-element constructs (pCasper) were made with CfAFP 337 isoform DNA using a strong constitutive promoter, Actin 5c. This is the first report of insect AFP used to transform another insect. Properly folded active insect AFP was only detected when signal sequences were used to target proteins to the endoplasmic reticulum for secretion into the hemolymph. The 18 residue Drosophila binding protein signal sequence (BiP) constructs resulted in transformed fly lines with significantly higher AFP expression in hemolymph than when the native C. fumiferana AFP signal sequence was used. The resultant transgene fly lines have the highest levels of thermal hysteresis, 0.8 degrees C, seen for any engineered Drosophila. Despite the high level of expression, even higher than some overwintering fish with natural levels of endogenous AFP, the transformants did not display any cold shock resistance compared to controls or low AFP expressing lines. These results indicate that insect AFP alone cannot protect Drosophila from cold shock and may not be useful for Drosophila cryopreservation.

Animals↗
PubMed2004

The Drosophila MOS ortholog is not essential for meiosis.

In metazoan oocytes, a metaphase arrest coordinates the completion of meiosis with fertilization. Vertebrate mos maintains the metaphase II arrest of mature oocytes and prevents DNA replication between the meiotic divisions. We identified a Drosophila homolog of mos and showed it to be the mos ortholog by two additional criteria. The dmos transcripts are present in Drosophila oocytes but not embryos, and injection of dmos into Xenopus embryos blocks mitosis and elevates active MAPK levels. In Drosophila, MAPK is activated in oocytes, consistent with a role in meiosis. We generated deletions of dmos and found that, as in vertebrates, dmos is responsible for the majority of MAPK activation. Unexpectedly, the oocytes that do mature complete meiosis normally and produce fertilized embryos that develop, although there is a reduction in female fertility and loss of some oocytes by apoptosis. Therefore, Drosophila contains a mos ortholog that activates a MAPK cascade during oogenesis and is nonessential for meiosis. This could be because there are redundant pathways regulating meiosis, because residual, low levels of active MAPK are sufficient, or because active MAPK is dispensable for meiosis in Drosophila. These results highlight the complexity of meiotic regulation that evolved to ensure accurate control over the reproductive process.

Amino Acid Sequence↗
PubMed2004

Drosophila, an emerging model for cardiac disease.

A variety of studies that are currently underway may validate the fruit fly as an in vivo model for analyzing genes involved in cardiac function. Many mutations in conserved genetic pathways have been found, including those controlling development and physiology. Because homologous genes control early developmental events as well as functional components of the Drosophila and vertebrate hearts, the fly is the simplest existing model system that can be used to assay genes involved in human congenital heart disease (CHD). The wide variety of genetic tools available to Drosophila researchers offers many technical advantages for rapidly screening through large numbers of candidate genes. Thus, an important future and long-term direction is likely to be the use of Drosophila as a vehicle for analyzing polygenic traits as an aid in human genetics. One can anticipate a time in the not too distant future when mutant lines exist for every gene in vertebrate systems, such as mice and zebrafish. However, one of the enduring problems that will not easily be addressed by such resources will be the tracking of complex traits defined by polygenic variants. For this level of genetic analysis, simple genetic model systems including yeast, Caenorhabditis elegans, and Drosophila melanogaster will undoubtedly play a crucial ongoing role. Of them, Drosophila will be critical for examining gene networks involved in organogenesis and is clearly the system of choice for studying cardiac development, function and aging, since among the simple genetic models it is the only one with a fluid pumping heart.

Animals↗
PubMed2006

Nutritional supplement chromium picolinate generates chromosomal aberrations and impedes progeny development in Drosophila melanogaster.

Chromium picolinate, [Cr(pic)(3)], is a popular nutritional supplement found in a variety of consumer products. Despite its popularity, safety concerns over its use have arisen. The supplement has been shown to generate clastogenic damage, mitochondrial damage, oxidative damage, and mutagenic effects in cultured cells and oxidative DNA damage and lipid peroxidation in rats. Recently [Cr(pic)(3)] has been demonstrated to generate heritable genetic change and delays in progeny development in Drosophila melanogaster. Based on the damage to chromosomes of cultured cells and of animal models, similar chromosome damage appeared to be a likely source of the mutagenic effects of the supplement in Drosophila. The current three-part study examines the effects of several chromium-containing supplements and their components on hatching and eclosion rates and success of development of first generation progeny of adult Drosophila fed food containing these compounds. It further examines the effects of the compounds on longevity of virgin male and female adults. Finally, the chromosomes in the salivary glands of Drosophila late in the third instar larval stage, which were the progeny of Drosophila whose diets were supplemented with nutritional levels of [Cr(pic)(3)], are shown to contain on average over one chromosomal aberration per two identifiable chromosomal arms. No aberrations were observed in chromosomes of progeny of untreated flies. The results suggest that human consumption of the supplement should be a matter of concern and continued investigation to provide insight into the requirements of chromium-containing supplements to give rise to genotoxic effects.

Animals↗
PubMed2006

A review of neurohormone GPCRs present in the fruitfly Drosophila melanogaster and the honey bee Apis mellifera.

G protein-coupled receptor (GPCR) genes are large gene families in every animal, sometimes making up to 1-2% of the animal's genome. Of all insect GPCRs, the neurohormone (neuropeptide, protein hormone, biogenic amine) GPCRs are especially important, because they, together with their ligands, occupy a high hierarchic position in the physiology of insects and steer crucial processes such as development, reproduction, and behavior. In this paper, we give a review of our current knowledge on Drosophila melanogaster GPCRs and use this information to annotate the neurohormone GPCR genes present in the recently sequenced genome from the honey bee Apis mellifera. We found 35 neuropeptide receptor genes in the honey bee (44 in Drosophila) and two genes, coding for leucine-rich repeats-containing protein hormone GPCRs (4 in Drosophila). In addition, the honey bee has 19 biogenic amine receptor genes (21 in Drosophila). The larger numbers of neurohormone receptors in Drosophila are probably due to gene duplications that occurred during recent evolution of the fly. Our analyses also yielded the likely ligands for 40 of the 56 honey bee neurohormone GPCRs identified in this study. In addition, we made some interesting observations on neurohormone GPCR evolution and the evolution and co-evolution of their ligands. For neuropeptide and protein hormone GPCRs, there appears to be a general co-evolution between receptors and their ligands. This is in contrast to biogenic amine GPCRs, where evolutionarily unrelated GPCRs often bind to the same biogenic amine, suggesting frequent ligand exchanges ("ligand hops") during GPCR evolution.

Animals↗
PubMed2006

What does Drosophila genetics tell us about speciation?

Studies of hybrid inviability, sterility and 'speciation genes' in Drosophila have given insight into the genetic changes that result in reproductive isolation. Here, I survey some extraordinary and important advances in Drosophila speciation research. However, 'reproductive isolation' is not the same as 'speciation', and this Drosophila work has resulted in a lopsided view of speciation. In particular, Drosophila are not always well-suited to investigating ecological and other selection-driven primary causes of speciation in nature. Recent advances have made use of far less tractable, but more charismatic organisms, such as flowering plants, vertebrates and larger insects. Work with these organisms has complemented Drosophila studies of hybrid unfitness to provide a more complete understanding of speciation.

Animals↗
PubMed2002

Gene targeting by homologous recombination: a powerful addition to the genetic arsenal for Drosophila geneticists.

A series of recent publications have firmly established the notion that Drosophila researchers now have a general method to subject genes for targeted modification by homologous recombination (HR) [Science 288 (2000) 2013; Genetics 157 (3) (2001) 1307; Genes Dev. 16 (12) (2002) 1568; Genetics 161 (2002) 1125-1136]. This method allows one to knockout essentially any gene starting with the DNA sequence of the gene. It has greatly enhanced studies of gene function as demonstrated by over 20 years of gene targeting practice in yeast and mouse. Here, I discuss the basic targeting methodology for eukaryotic organisms. I compare the Drosophila method with the traditional targeting scheme in yeast and mouse mainly to show that the targeting mechanism as well as many aspects of the experimental design remain unchanged, and that the Drosophila scheme differs only in the way in which the donor molecule for targeting is generated. I propose that the Drosophila method can be readily adapted in other organisms without culturable stem cells, since the mechanism for in vivo donor generation in Drosophila is likely to be functional in a variety of different organisms.

Animals↗
PubMed2003

Insulin stimulates glucose metabolism via the pentose phosphate pathway in Drosophila Kc cells.

Drosophila melanogaster has become a prominent and convenient model for analysis of insulin action. However, to date very little is known regarding the effect of insulin on glucose uptake and metabolism in Drosophila. Here we show that, in contrast to effects seen in mammals, insulin did not alter [(3)H]2-deoxyglucose uptake and in fact decreased glycogen synthesis ( approximately 30%) in embryonic Drosophila Kc cells. Insulin significantly increased ( approximately 1.5-fold) the production of (14)CO(2) from D-[1-(14)C]glucose while the production of (14)CO(2) from D-[6-(14)C]glucose was not altered. Thus, insulin-stimulated glucose oxidation did not occur via increasing Krebs cycle activity but rather by stimulating the pentose phosphate pathway. Indeed, inhibition of the oxidative pentose phosphate pathway by 6-aminonicotinamide abolished the effect of insulin on (14)CO(2) from D-[U-(14)C]glucose. A corresponding increase in lactate production but no change in incorporation of D-[U-(14)C]glucose into total lipids was observed in response to insulin. Glucose metabolism via the pentose phosphate pathway may provide an important source of 5'-phosphate for DNA synthesis and cell replication. This novel observation correlates well with the fact that control of growth and development is the major role of insulin-like peptides in Drosophila. Thus, although intracellular signaling is well conserved, the metabolic effects of insulin are dramatically different between Drosophila and mammals.

6-Aminonicotinamide↗
PubMed2003

Drosophila melanogaster, a genetic model system for alcohol research.

In its natural environment, which consists of fermenting plant materials, the fruit fly Drosophila melanogaster encounters high levels of ethanol. Flies are well equipped to deal with the toxic effects of ethanol; they use it as an energy source and for lipid biosynthesis. The primary ethanol-metabolizing pathway in flies involves the enzymes alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH); their role in adaptation to ethanol-rich environments has been studied extensively. The similarity between Drosophila and mammals is not restricted to the manner in which they metabolize ethanol; behaviors elicited by ethanol exposure are also remarkably similar in these organisms. Flies show signs of acute intoxication, which range from locomotor stimulation at low doses to complete sedation at higher doses, they develop tolerance upon intermittent ethanol exposure, and they appear to like ethanol, showing preference for ethanol-containing media. Molecular genetic analysis of ethanol-induced behaviors in Drosophila, while still in its early stages, has already revealed some surprising parallels with mammals. The availability of powerful tools for genetic manipulation in Drosophila, together with the high degree of conservation at the genomic level, make Drosophila a promising model organism to study the mechanism by which ethanol regulates behavior and the mechanisms underlying the organism's adaptation to long-term ethanol exposure.

Alcohol Dehydrogenase↗
PubMed2002

Neuropeptides in the nervous system of Drosophila and other insects: multiple roles as neuromodulators and neurohormones.

Neuropeptides in insects act as neuromodulators in the central and peripheral nervous system and as regulatory hormones released into the circulation. The functional roles of insect neuropeptides encompass regulation of homeostasis, organization of behaviors, initiation and coordination of developmental processes and modulation of neuronal and muscular activity. With the completion of the sequencing of the Drosophila genome we have obtained a fairly good estimate of the total number of genes encoding neuropeptide precursors and thus the total number of neuropeptides in an insect. At present there are 23 identified genes that encode predicted neuropeptides and an additional seven encoding insulin-like peptides in Drosophila. Since the number of G-protein-coupled neuropeptide receptors in Drosophila is estimated to be around 40, the total number of neuropeptide genes in this insect will probably not exceed three dozen. The neuropeptides can be grouped into families, and it is suggested here that related peptides encoded on a Drosophila gene constitute a family and that peptides from related genes (orthologs) in other species belong to the same family. Some peptides are encoded as multiple related isoforms on a precursor and it is possible that many of these isoforms are functionally redundant. The distribution and possible functions of members of the 23 neuropeptide families and the insulin-like peptides are discussed. It is clear that each of the distinct neuropeptides are present in specific small sets of neurons and/or neurosecretory cells and in some cases in cells of the intestine or certain peripheral sites. The distribution patterns vary extensively between types of neuropeptides. Another feature emerging for many insect neuropeptides is that they appear to be multifunctional. One and the same peptide may act both in the CNS and as a circulating hormone and play different functional roles at different central and peripheral targets. A neuropeptide can, for instance, act as a coreleased signal that modulates the action of a classical transmitter and the peptide action depends on the cotransmitter and the specific circuit where it is released. Some peptides, however, may work as molecular switches and trigger specific global responses at a given time. Drosophila, in spite of its small size, is now emerging as a very favorable organism for the studies of neuropeptide function due to the arsenal of molecular genetics methods available.

Amino Acid Sequence↗
PubMed2000

Complementary DNA structure and genomic organization of Drosophila menin.

Menin is a protein product of a tumor supressor gene MEN1, mutations of which are responsible for multiple endocrine neoplasia type 1, an autosomal dominant familial cancer syndrome. We determined the nucleotide sequence of the Drosophila menin cDNA using RT-PCR and RACE, and confirmed it by direct sequencing of genomic DNA. Gene expression of Drosophila menin was detected by Northern blot analysis in adult and embryo as two types of transcripts, one identical in size to the cDNA, and the other larger but detected only in embryo. The Drosophila menin gene was composed of five exons in which the protein was encoded in exon 2 through 5, and spanned approximately 6.3 kb. The deduced amino acid (AA) sequence of Drosophila menin consisted of 751 AAs with a calculated molecular mass of 81.7 kDa, and showed 44-47% identity to human, rat, mouse and zebrafish menin over the entire length. Among the AA residue substitutions that have been reported as disease-associated missense mutations and single AA deletions, 53 out of 71 were completely conserved in Drosophila. The presence of menin ortholog in insect indicates that menin is an evolutionally conserved protein with a fundamental role in biological processes.

Amino Acid Sequence↗
PubMed1998

Laminin-dependent integrin clustering with tyrosine-phosphorylated molecules in a Drosophila neuronal cell line.

To gain more insight into the molecular and cellular aspects of basement membranes during Drosophila morphogenesis, especially in neural development, we carried out cell biological screening to establish a cell culture system in which Drosophila cell-matrix interaction could be reconstituted. The screening showed that a Drosophila neuronal cell line, BG2-c6, established from the third-instar larval central nervous system, had a strong adhesion activity when purified Drosophila laminin was used as a substrate. Outgrowth of axon-like structures was stimulated on laminin. Histochemical analysis revealed clusters of integrin together with phosphotyrosine and alpha-actinin. These data indicate that the Drosophila integrin cascade triggered by the interaction between BG2-c6 and laminin was initiated at the integrin cluster with tyrosine-phosphorylated proteins, similar to the observations in vertebrate cells.

Animals↗
PubMed2002

A calpain-like activity insensitive to calpastatin in Drosophila melanogaster.

Calpains are neutral Ca2+-dependent cysteine proteases. In this study, we utilized casein zymography to detect such a proteolytic activity in Drosophila melanogaster extracts throughout the life of this organism. One calpain-like activity that was sensitive to the general cysteine protease inhibitors, E64 and calpain inhibitor I, but insensitive to the human calpain-specific inhibitor, calpastatin, is demonstrated. The relevance of this finding is discussed with respect to the absence of a corresponding Drosophila gene, homologous to the vertebrate calpastatin genes, as concluded from our unsuccessful attempts to clone such a gene and our Blast searches using the FlyBase. The mechanisms of Drosophila calpain regulation require further investigation. However, we suggest that single chain, non-heterodimeric calpains may be insensitive to calpastatin and that Drosophila cystatin-like molecules may play a role in negatively regulating Drosophila calpain.

Animals↗
PubMed2002

Drosophila acid DNase is a homolog of mammalian DNase II.

Mammalian DNase II enzymes and the Caenorhabditis elegans homolog NUC-1 have recently been shown to be critically important during engulfment-mediated clearance of DNA. In this report, we describe the cloning and characterization of the gene encoding Drosophila DNase II. Database queries using the C. elegans NUC-1 protein sequence identified a highly homologous open reading frame in Drosophila (CG7780) that could encode a similar enzyme. Analysis of crude protein extracts revealed that wild-type Drosophila contain a potent acid endonuclease activity with cleavage preferences similar to DNase II/NUC1, while the same activity was markedly reduced in an acid DNase hypomorphic mutant line. Furthermore, the pattern of cleavage products generated from an end-labeled substrate by hypomorphic-line extracts was significantly altered in comparison to the pattern generated by wild-type extracts. Sequence analysis of CG7780 DNA and mRNA revealed that the hypomorphic line contains a missense mutation within the coding region of this gene. Additionally, Northern analysis demonstrated that CG7780 expression is normal in the mutant line, which in combination with the lowered/altered enzymatic activity and sequencing data suggested a defect in the CG7780 protein. To conclusively determine if CG7780 encoded the Drosophila equivalent of DNase II/NUC-1, transgenic lines expressing wild-type CG7780 in the mutant background were generated and subsequently shown to complement the mutant phenotype. Our results, therefore, provide compelling evidence that the predicted gene CG7780 encodes Drosophila DNase II (dDNase II), an enzyme related in sequence and activity to mammalian DNase II. Interestingly, overexpression of CG7780 both ubiquitously and in specific tissues failed to elicit any discernable phenotype.

Amino Acid Sequence↗
PubMed1997

Cloning and expression analysis of a novel mouse gene with sequence similarity to the Drosophila fat facets gene.

The Drosophila fat facets (faf) gene is a ubiquitin-specific protease necessary for the normal development of the eye and of the syncytial stage embryo in the fly. Using a gene trap approach in embryonic stem cells we have isolated a murine gene with extensive sequence similarity to the Drosophila faf gene and called it Fam (fat facets in mouse). The putative mouse protein shows colinearity and a high degree of sequence identity to the Drosophila protein over almost its entire length of 2554 amino acids. The two enzymatic sites characteristic of ubiquitin-specific proteases are very highly conserved between mice and Drosophila and this conservation extends to yeast. Fam is expressed in a complex pattern during postimplantation development. In situ hybridisation detected Fam transcripts in the rapidly expanding cell populations of gastrulating and neurulating embryos, in post-mitotic cells of the CNS as well as in the apoptotic regions between the digits, indicating that it is not associated with a single developmental or cellular event. The strong sequence similarity to faf and the developmentally regulated expression pattern suggest that Fam and the ubiquitin pathway may play a role in determining cell fate in mammals, as has been established for Drosophila.

Amino Acid Sequence↗
PubMedDate not supplied

Transcriptional regulation of hematopoiesis in Drosophila.

As in mammals, blood cells in Drosophila are derived from a common multipotent hematopoietic precursor population. In the embryo, these precursors are derived from the head mesoderm, whereas larval hematopoietic precursors are found in a specialized organ called the lymph gland. This shift in location of hematopoietic differentiation is reminiscent of similar events that occur during mammalian development. Recent analysis has identified several transcriptional regulators in Drosophila that influence hematopoietic lineage commitment. Interestingly, many of these factors are similar to factors directing mammalian hematopoietic differentiation. Although Drosophila blood cells are much less varied in terms of specific lineages, it would appear that many mechanistic aspects by which hematopoietic cell fate is determined have been conserved between Drosophila and mammals. Herein, we describe the Drosophila blood cell types, their physical origin, and the transcriptional regulators that govern this process.

Animals↗