Specific age related signatures in Drosophila body parts transcriptome

BACKGROUND: During the last two decades progress in the genetics of aging in invertebrate models such as C. elegans and D. melanogaster has clearly demonstrated the existence of regulatory pathways that control the rate of aging in these organisms, such as the insulin-like pathway, the Jun kinase pathway and the Sir2 deacetylase pathway. Moreover, it was rapidly shown that some of these pathways are conserved from yeast to humans. In parallel to genetic studies, genomic expression approches have given us significant information on the gene expression modifications that occur during aging either in wild type or long-lived mutant animals. But most of the genomic studies of invertebrate models have been performed so far on whole animals, while several recent studies in mammals have shown that the effects of aging are tissue specific. RESULTS: We used oligonucleotide microarrays to address the specificities of transcriptional responses in aging Drosophila in head, thorax or whole body. These fly parts are enriched in transcripts that represent different and complementary sets of genes. We present evidence for both specific and common transcriptional responses during the aging process in these tissues. About half of the genes described as downregulated with age are linked to reproduction and enriched in gonads. Greater downregulation of mitochondrial genes, activation of the JNK pathway and upregulation of proteasome subunits in the thorax of aged flies all suggest that muscle may be particularly sensitive to aging. Simultaneous age-related impairment of synaptic transmission gene expression is observed in fly heads. In addition, a detailed comparison with other microarray data indicates that in aged flies there are significant deviations from the canonical responses to oxidative stress and immune stress. CONCLUSION: Our data demonstrates the advantages and value of regionalized and comparative analysis of gene expression in aging animals. Adding to the age-regulated genes already identified in whole animal studies, it provides lists of new regionalized genes to be studied for their functional role in the aging process. This work also emphasizes the need for such experiments to reveal in greater detail the consequences of the transcriptional modifications induced by aging regulatory pathways

Lessons from the analysis of nonhuman primates for understanding human aging and neurodegenerative diseases

Animal models are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates. Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher. Despite these caveats, considerable scientific advances have been possible using nonhuman primates. This review concisely summarizes their role in the study of aging and of the mechanisms involved in neurodegenerative disorders associated mainly with cognitive dysfunctions (Alzheimer’s and prion diseases) or motor deficits (Parkinson’s and related diseases)

Combining Gene Transfer and Nonhuman Primates to Better Understand and Treat Parkinson’s Disease

Parkinson's disease (PD) is a progressive CNS disorder that is primarily associated with impaired movement. PD develops over decades and is linked to the gradual loss of dopamine delivery to the striatum, via the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). While the administration of L-dopa and deep brain stimulation are potent therapies, their costs, side effects and gradual loss of efficacy underlines the need to develop other approaches. Unfortunately, the lack of pertinent animal models that reproduce DA neuron loss and behavior deficits-in a timeline that mimics PD progression-has hindered the identification of alternative therapies. A complementary approach to transgenic animals is the use of nonhuman primates (NHPs) combined with the overexpression of disease-related genes using viral vectors. This approach may induce phenotypes that are not influenced by developmental compensation mechanisms, and that take into account the personality of animals. In this review article, we discuss the combination of gene transfer and NHPs to develop "genetic" models of PD that are suitable for testing therapeutic approaches

Le développement des corps pédonculés chez Drosophila Melanogaster : Rôle des protéines tyrosine kinases SRC64 et linotte dans la croissance et le guidage des axones

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Gain-of-function screen identifies a role of the Src64 oncogene in Drosophila mushroom body development

International audienceMushroom bodies (MB) are substructures in the Drosophila brain that are essential for memory. At present, MB anatomy is rather well described when compared to other brain areas, and elucidation of the genetic control of the development and projection patterns of MB neurons will be important to the understanding of their functions. We have performed a gain-of-function screen in order to identify genes that are involved in MB development. We drove expression of genes in MB neurons by crossing 2407 GAL4-driven UY element lines to lines containing an MB GAL4 source and UAS-GFP elements, and looked for defects in the MB structure. We have molecularly identified the genomic regions adjacent to the 26 positive UY insertions and found 18 potential genes that exhibit adult MB gain-of-function phenotypes. The proteins encoded by these candidate genes include, as well as genes with yet unknown function, transcription factors (e.g., tramtrack), nanos RNA-binding protein, microtubule-severing protein, vesicle trafficking proteins, axon guidance receptor, and the Src64 cytoplasmic protein tyrosine kinase. These genes are involved in key features of neuron cell biology. In three cases, tramtrack, nanos, and Src64, we show that the open reading frame located directly downstream of the UY P element is indeed the expressed target gene. Loss-of-function mutations of both ttk and Src64 lead to MB phenotypes proving that these genes are involved in the genetic control of MB development. Moreover, Src64 is shown here to act in a cell-autonomous fashion and is likely to interact with the previously-identified linotte/derailed receptor tyrosine kinase in MB development

Courtship behaviour of Drosophila melanogaster revisited

0003-3472 doi: DOI: 10.1016/j.anbehav.2006.01.027Nearly all studies of Drosophila melanogaster courtship have focused exclusively on male behaviour. Female precopulatory behaviour is often relegated to ‘accept' or ‘reject' mating, and how female behaviour interacts with that of males remains largely unknown. Using a video-computing approach, we measured 10 behavioural states and 22 elementary behaviours that occur during the precopulatory phase of Canton-S (Cs) flies. Male and female behaviours were studied under a variety of social conditions. This allowed us to identify which one(s) is relevant to courtship or to general activity. Our analysis showed that the courtship repertoire was not constant over time, as female and male behaviours varied during courtship, and that virgin Cs females showed several behavioural sequences whose frequency, latency and total duration could predict their mating success. The most striking index of females' willingness to copulate was the way they extruded the ovipositor: a partial extrusion stimulated male courtship, whereas total extrusion inhibited it. Furthermore, females that mated preened their abdomen more frequently than did females that did not mate. We also observed that male sexual activity was strongly increased when the female emitted a tiny volatile droplet at the tip of the ovipositor. We hypothesized that partial ovipositor extrusion, droplet emission and abdominal preening are related behaviours that result in the active dispersion of compounds spread on the female's abdomen. Such a detailed picture of the precopulatory behaviours should allow better characterization of the sensory stimuli exchanged during courtship in Drosophila

Respective roles of the DRL receptor and its ligand WNT5 in Drosophila mushroom body development.

International audienceIn recent decades, Drosophilamushroom bodies (MBs) have become a powerful model for elucidating the molecular mechanismsunderlying brain development and function. We have previously characterized the derailed(drl; also known as linotte) receptortyrosine kinase as an essential component of adult MB development. Here we show, using MARCM clones, a non-cell-autonomousrequirement for the DRL receptor in MB development. This result is in accordance with the pattern of DRL expression, which occursthroughout development close to, but not inside, MB cells. While DRL expression can be detected within both interhemispheric glialand commissural neuronal cells, rescue of the drlMB defects appears to involve the latter cellular type. The WNT5 protein has beenshown to act as a repulsive ligand for the DRL receptor in the embryonic central nervous system. We show here that WNT5 isrequired intrinsically within MB neurons for proper MB axonal growth and probably interacts with the extrinsic DRL receptor inorder to stop axonal growth. We therefore propose that the neuronal requirement for both proteins defines an interactingnetwork acting during MB development

Pollen waste and unrelated traits in fig-fig wasp symbiosis: a new behaviour duggesting a host shift

In a fig–fig wasp symbiosis, we have discovered that male fig pollinators (Alfonsiella fimbriata Waterston) bite into the dehiscent anthers of Ficus natalensis leprieuri Miq., thus scattering the pollen grains throughout the syconium. Female pollinators are the only ones to transfer pollen to conspecific trees, and collect pollen actively from the anthers only. Thus, this male behaviour appears to be antagonistic to the pollination process. We compare different wasp pollinating behaviours between fig species exhibiting dehiscent and non-dehiscent anthers and conclude that this male behaviour is new and not required with spontaneously dehiscent anthers. These findings could suggest a host shift of Alfonsiella fimbriat

The steroid hormone receptor EcR finely modulates Drosophila lifespan during adulthood in a sex-specific manner

International audienc

FGF1 protects neuroblastoma SH-SY5Y cells from p53-dependent apoptosis through an intracrine pathway regulated by FGF1 phosphorylation

International audienceNeuroblastoma, a sympathetic nervous system tumor, accounts for 15% of cancer deaths in children. In contrast to most human tumors, p53 is rarely mutated in human primary neuroblastoma, suggesting impaired p53 activation in neuroblastoma. Various studies have shown correlations between fgf1 expression levels and both prognosis severity and tumor chemoresistance. As we previously showed that fibroblast growth factor 1 (FGF1) inhibited p53-dependent apoptosis in neuron-like PC12 cells, we initiated the study of the interaction between the FGF1 and p53 pathways in neuroblastoma. We focused on the activity of either extracellular FGF1 by adding recombinant rFGF1 in media, or of intracellular FGF1 by overexpression in human SH-SY5Y and mouse N2a neuroblastoma cell lines. In both cell lines, the genotoxic drug etoposide induced a classical mitochondrial p53dependent apoptosis. FGF1 was able to inhibit p53-dependent apoptosis upstream of mitochondrial events in SH-SY5Y cells by both extracellular and intracellular pathways. Both rFGF1 addition and etoposide treatment increased fgf1 expression in SH-SY5Y cells. Conversely, rFGF1 or overexpressed FGF1 had no effect on p53-dependent apoptosis and fgf1 expression in neuroblastoma N2a cells. Using different FGF1 mutants (that is, FGF1 K132E , FGF1 S130A and FGF1 S130D), we further showed that the C-terminal domain and phosphorylation of FGF1 regulate its intracrine anti-apoptotic activity in neuroblastoma SH-SY5Y cells. This study provides the first evidence for a role of an intracrine growth factor pathway on p53-dependent apoptosis in neuroblastoma, and could lead to the identification of key regulators involved in neuroblastoma tumor progression and chemoresistance