1,721,069 research outputs found
Beyond pathology: APP, brain development and Alzheimer's disease
No full textAlzheimer's disease (AD) is the most common form of dementia among the elderly. Research in the AD field has been mostly focused on the biology of the Aβ peptide but increasing evidence is shifting attention toward the physiological role of APP as key to understanding AD pathology. It is becoming apparent that APP plays a central role in the mechanisms that guarantee the accuracy and the robustness of brain wiring. In the present review we explore APP functions with focus on some of the underlying molecular mechanisms
Author response
Full text linkDetecting pathogens and mounting immune responses upon infection is crucial for animal health. However, these responses come at a high metabolic price (McKean and Lazzaro, 2011, Kominsky et al., 2010), and avoiding pathogens before infection may be advantageous. The bacterial endotoxins lipopolysaccharides (LPS) are important immune system infection cues (Abbas et al., 2014), but it remains unknown whether animals possess sensory mechanisms to detect them prior to infection. Here we show that Drosophila melanogaster display strong aversive responses to LPS and that gustatory neurons expressing Gr66a bitter receptors mediate avoidance of LPS in feeding and egg laying assays. We found the expression of the chemosensory cation channel dTRPA1 in these cells to be necessary and sufficient for LPS avoidance. Furthermore, LPS stimulates Drosophila neurons in a TRPA1-dependent manner and activates exogenous dTRPA1 channels in human cells. Our findings demonstrate that flies detect bacterial endotoxins via a gustatory pathway through TRPA1 activation as conserved molecular mechanism.sponsorship: Vlaams Instituut voor Biotechnologie Alessia Soldano Luis Franco Guangda Liu Natalia Mora Emre Yaksi Bassem A Hassanr Fonds Wetenschappelijk Onderzoek G.0702.12 Alessia Soldano Yeranddy A Alpizar Brett Boonen Alejandro Lopez-Requena Natalia Mora Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talaverar Fonds Wetenschappelijk Onderzoek G.0077.15 Alessia Soldano Yeranddy A Alpizar Brett Boonen Alejandro Lopez-Requena Natalia Mora Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talaverar Fonds Wetenschappelijk Onderzoek G.0680.10 Alessia Soldano Yeranddy A Alpizar Brett Boonen Alejandro Lopez-Requena Natalia Mora Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talaverar Fonds Wetenschappelijk Onderzoek G.0681.10 Alessia Soldano Yeranddy A Alpizar Brett Boonen Alejandro Lopez-Requena Natalia Mora Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talaverar Fonds Wetenschappelijk Onderzoek G.0503.12 Alessia Soldano Yeranddy A Alpizar Brett Boonen Alejandro Lopez-Requena Natalia Mora Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talaverar Fonds Wetenschappelijk Onderzoek G.0654.15 Alessia Soldano Yeranddy A Alpizar Brett Boonen Alejandro Lopez-Requena Natalia Mora Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talaverar Fonds Wetenschappelijk Onderzoek G.0761.10N Alessia Soldano Yeranddy A Alpizar Brett Boonen Alejandro Lopez-Requena Natalia Mora Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talaverar Fonds Wetenschappelijk Onderzoek G.0596.12 Alessia Soldano Yeranddy A Alpizar Brett Boonen Alejandro Lopez-Requena Natalia Mora Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talaverar Fonds Wetenschappelijk Onderzoek G.0565.07 Alessia Soldano Yeranddy A Alpizar Brett Boonen Alejandro Lopez-Requena Natalia Mora Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talaverar KU Leuven GOA/14/011 Alessia Soldano Yeranddy A Alpizar Brett Boonen Luis Franco Alejandro Lopez-Requena Guangda Liu Natalia Mora Emre Yaksi Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talaverar European Commission IUAP P7/13 Alessia Soldano Yeranddy A Alpizar Brett Boonen Luis Franco Alejandro Lopez-Requena Guangda Liu Natalia Mora Emre Yaksi Thomas Voets Rudi Vennekensr KU Leuven OT/12/091 Alessia Soldano Yeranddy A Alpizar Brett Boonen Luis Franco Alejandro Lopez-Requena Guangda Liu Natalia Mora Emre Yaksi Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talaverar KU Leuven PF-TRPLe Alessia Soldano Yeranddy A Alpizar Brett Boonen Luis Franco Alejandro Lopez-Requena Guangda Liu Natalia Mora Emre Yaksi Thomas Voets Rudi Vennekens Bassem A Hassan Karel Talavera (Vlaams Instituut voor Biotechnologie, Fonds Wetenschappelijk Onderzoek|G.0702.12, Fonds Wetenschappelijk Onderzoek|G.0077.15, Fonds Wetenschappelijk Onderzoek|G.0680.10, Fonds Wetenschappelijk Onderzoek|G.0681.10, Fonds Wetenschappelijk Onderzoek|G.0503.12, Fonds Wetenschappelijk Onderzoek|G.0654.15, Fonds Wetenschappelijk Onderzoek|G.0761.10N, Fonds Wetenschappelijk Onderzoek|G.0596.12, KU Leuven|GOA/14/011, KU Leuven|OT/12/091, European Commission|IUAP P7/13, KU Leuven PF-TRPLe)status: Publishe
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Genes expressed in specific areas of the human fetal cerebral cortex display distinct patterns of evolution.
Full text linkThe developmental mechanisms through which the cerebral cortex increased in size and complexity during primate evolution are essentially unknown. To uncover genetic networks active in the developing cerebral cortex, we combined three-dimensional reconstruction of human fetal brains at midgestation and whole genome expression profiling. This novel approach enabled transcriptional characterization of neurons from accurately defined cortical regions containing presumptive Broca and Wernicke language areas, as well as surrounding associative areas. We identified hundreds of genes displaying differential expression between the two regions, but no significant difference in gene expression between left and right hemispheres. Validation by qRTPCR and in situ hybridization confirmed the robustness of our approach and revealed novel patterns of area- and layer-specific expression throughout the developing cortex. Genes differentially expressed between cortical areas were significantly associated with fast-evolving non-coding sequences harboring human-specific substitutions that could lead to divergence in their repertoires of transcription factor binding sites. Strikingly, while some of these sequences were accelerated in the human lineage only, many others were accelerated in chimpanzee and/or mouse lineages, indicating that genes important for cortical development may be particularly prone to changes in transcriptional regulation across mammals. Genes differentially expressed between cortical regions were also enriched for transcriptional targets of FoxP2, a key gene for the acquisition of language abilities in humans. Our findings point to a subset of genes with a unique combination of cortical areal expression and evolutionary patterns, suggesting that they play important roles in the transcriptional network underlying human-specific neural traits.Journal ArticleResearch Support, Non-U.S. Gov'tValidation StudiesSCOPUS: ar.jinfo:eu-repo/semantics/publishe
Ontwikkeling van Nieuwe Tools voor de Studie van Atonal tijdens Neurogenese
No full textDuring early neural development, progenitor cells participate in regulat ory pathways that involve cell fate decision and tissue patterning. Alth ough many factors of these regulatory pathways are known and studied, a lot of them still remain unidentified. We use Drosophila as a model organism to find and investigate the molecular mechanisms that con trol early neurogenesis. Drosophila is an excellent model organism to study and screen for mutant s involved in neurogenesis. Its peripheral nervous system (PNS) has exte rnal features that allow easy scoring for mutations that affect normal d evelopment. Drosophila bristles (external part of the sensory organ), an d the Drosophila compound eye have been used extensively to look for and study mutations affecting normal neuronal development. In this work we are studying ato, a proneural gene in Drosophila. D espite the fact that we know when and where ato genes are required in th e Drosophila peripheral nervous system and how they interact with Notch signaling to select sensory organ precursors (SOP), the mechanisms that mediate their activity within SOPs and their specificity in inducing neu ronal differentiation remain largely unknown. We performed a computation ally supported genetic screen to find dominant modifiers of Ato. First w e validated this computational based prioritization method, called HIGHF LY-ENDEAVOUR and showed that biologically meaningful prioritizations cou ld be obtained, secondly we used it to prioritize genes located in defic iencies (large deletions) that dominantly modified ato. Thus we wer e able to retrieve the genes responsible for this modification, finding 18 dominant modifiers of ato. The second aim of this work was to create a tool to study ato in it s endogenous locus by exchanging ato, through ends out homologous recomb ination, with an RMCE docking site. This RMCE docking site allows effici ent targeting of the ato locus and we obtained an overall efficiency of 10%. We used this tool, which we called IMAGO (Integrase-Med iated Approach for Gene Knock-Out) to target ato with a construct that allows the generation of postmitotic clones i n Drosophila.status: Publishe
Regulatie van de dynamiek van de neurieten van Drosophila melanogaster tijdens de ontwikkeling an na een beschadiging
No full textThe integration of a neuron in a functional circuit relies on the controlled formation of neurites. Neurites are the axonal and dendritic processes by which these highly specialized cells perceive and relay information. In mammalian systems a common mechanism to establish circuits is refinement of excessive projections during development. However, mechanisms of exuberant neurite refinement are largely unknown. In this work, we show that an adult specific neuronal circuit in the central visual system of Drosophila shows excessive axon branch formation and subsequent pruning during brain development. Subsequently, we analyzed the mechanisms of this developmental refinement. We find that dosage critical activation of asymmetrically distributed Epidermal Growth Factor Receptor (EGFR) by ligand released from retinal axons is necessary for branch pruning. Live imaging of the developing brain shows that EGFR signaling is required for branch growth and retraction dynamics, likely through regulation of the actin cytoskeleton. These observations establish the first Drosophila model for developmental neuronal circuit refinement in the central nervous system (CNS) and identify non-canonical localized EGFR signaling as a novel refinement mechanism. Disruption of axonal processes in the adult leads to the loss of information transfer and therefore to dysfunctions of the nervous system. To recover functionality of injured neurons, axons first need to re-initiate axon growth similar to axon formation during development. The capacity of CNS neurons to re-grow is severely reduced, in contrast to their counterparts in the peripheral nervous system.Two major causes of this inability are the inhibitory CNS environment and the loss of the intrinsic capacity to grow. Many studies focused on the inhibitory CNS environment but successful manipulation to achieve robust regeneration is still missing. Therefore increasing efforts are undertaken to uncover novel factors to enhance the intrinsic growth capacity. To this end, we conducted the first adult CNS injury screen in invertebrates using a Drosophila regeneration assay developed in our laboratory. With a targeted gain-of-function pre-screen of approximately 330 genes, we first identify 30 modulators of developmental outgrowth. Subsequently, genes with growth enhancing properties were tested in the regeneration assay. We show that genetic manipulations of three different transcription factors (Kay, Pdm2 and Sens) and a gene involved in protein turnover (faf) can enhance the regenerative response of injured axons from a small subpopulation of CNS neurons (sLNv). We prove that these factors can robustly increase the amount of brains showing a regenerative responseand significantly enhance the length these axons can grow after injury.status: Publishe
Analysen van de functie van basic Helix-loop-Helix proteinen bij de ontwikkeling van het Drosophila melanogaster zenuwstelsel
No full textstatus: Publishe
- …
