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Publications (72)
As the first member of the solute carrier 6 (SLC6) protein family, the γ-aminobutyric acid (GABA) transporter 1 (GAT1, SLC6A1 ), plays a pivotal role in the uptake of GABA from the synaptic cleft into neurons and astrocytes. This process facilitates the subsequent storage of GABA in presynaptic vesicles. The human SLC6A1 gene is highly susceptible...
The antidepressants trazodone and nefazodone were approved some 4 and 3 decades ago, respectively. Their action is thought to be mediated, at least in part, by inhibition of the serotonin transporter [SERT/solute carrier (SLC)-6A4]. Surprisingly, their mode of action on SERT has not been characterized. Here, we show that, similar to the chemically...
Mutations in the human γ-aminobutyric acid (GABA) transporter 1 (hGAT-1) can instigate myoclonic-atonic and other generalized epilepsies in the afflicted individuals. We systematically examined fifteen hGAT-1 disease variants, all of which dramatically reduced or completely abolished GABA uptake activity. Many of these loss-of-function variants wer...
The serotonin transporter (SERT/SLC6A4) is arguably the most extensively studied solute carrier (SLC). During its eponymous action - i.e., the retrieval of serotonin from the extracellular space - SERT undergoes a conformational cycle. Typical inhibitors (antidepressant drugs and cocaine), partial and full substrates (amphetamines and their derivat...
The human γ-aminobutyric acid (GABA) transporter 1 (hGAT-1) is the first member of the solute carrier 6 (SLC6) protein superfamily. GAT-1 (SLC6A1) is one of the main GABA transporters in the central nervous system. Its principal physiological role is retrieving GABA from the synapse into neurons and astrocytes, thus swiftly terminating neurotransmi...
One hallmark of the visual system is a strict retinotopic organization from the periphery toward the central brain, where functional imaging in Drosophila revealed a spatially accurate representation of visual cues in the central complex. This raised the question how, on a circuit level, the topographic features are implemented, as the majority of...
One hallmark of the visual system is a strict retinotopic organization from the periphery toward the central brain, where functional imaging in Drosophila revealed a spatially accurate representation of visual cues in the central complex. This raised the question how, on a circuit level, the topographic features are implemented, as the majority of...
Missense mutations that give rise to protein misfolding are rare, but collectively, defective protein folding diseases are consequential. Folding deficiencies are amenable to pharmacological correction (pharmacochaperoning), but the underlying mechanisms remain enigmatic. Ibogaine and its active metabolite noribogaine correct folding defects in the...
Neurodegenerative disorders (nD) like Alzheimer’s (AD), parkinson’s (pD), Huntington’s or prion diseases share similar pathological features. They are all age dependent and are often associated with disruptions in analogous metabolic processes such as protein aggregation and oxidative stress, both of which involve metal ions like copper, manganese...
Missense mutations that give rise to protein misfolding are rare, but collectively, defective protein folding diseases are consequential. Folding deficiencies are amenable to pharmacological correction (pharmacochaperoning), but the underlying mechanisms remain enigmatic. Ibogaine and its active metabolite noribogaine correct folding defects in the...
One hallmark of the visual system is the strict retinotopic organization from the periphery towards the central brain, spanning multiple layers of synaptic integration. Recent Drosophila studies on the computation of distinct visual features have shown that retinotopic representation is often lost beyond the optic lobes, due to convergence of colum...
Interhemispheric synaptic connections, a prominent feature in animal nervous systems for the rapid exchange and integration of neuronal information, can appear quite suddenly during brain evolution, raising the question about the underlying developmental mechanism. Here, we show in the Drosophila olfactory system that the induction of a bilateral s...
Olfactory systems across the animal kingdom show astonishing similarities in their morphological and functional organization. In mouse and Drosophila, olfactory sensory neurons are characterized by the selective expression of a single odorant receptor (OR) type and by the OR class-specific connection in the olfactory brain center. Monospecific OR e...
The serotonin transporter (SERT) regulates serotonergic neurotransmission by retrieving released serotonin and replenishing vesicular stores. SERT is not only delivered to axons but it is also present on the neuronal soma and on dendrites. It has not been possible to restrict the distribution of SERT without affecting transporter function. Hence, t...
Neurons are highly polarized cells with distinct protein compositions in axonal and dendritic compartments. Cellular mechanisms controlling polarized protein sorting have been described for mature nervous system but little is known about the segregation in newly differentiated neurons. In a forward genetic screen for regulators of Drosophila brain...
The brain of Drosophila melanogaster is comprised of some 100,000 neurons, 127 and 80 of which are dopaminergic and serotonergic, respectively. Their activity regulates behavioral functions equivalent to those in mammals, e.g., motor activity, reward and aversion, memory formation, feeding, sexual appetite, etc. Mammalian dopaminergic and serotoner...
The brain of Drosophila melanogaster is comprised of some 100,00 neurons, 127 and 80 of which are dopaminergic and serotonergic, respectively. Their activity regulates behavioral functions equivalent to those in mammals, e.g. motor activity, reward and aversion, memory formation, feeding, sexual appetite etc. Mammalian dopaminergic and serotonergic...
Point mutations in the gene encoding the human dopamine transporter (hDAT, SLC6A3) cause a syndrome of infantile/juvenile dystonia and parkinsonism. To unravel the molecular mechanism underlying these disorders and investigate possible pharmacological therapies, here we examined 13 disease-causing DAT mutants that were retained in the endoplasmic r...
The visual system is characterized by a strict topographic organization from the retina towards multiple layers of synaptic integration. Recent studies in Drosophila have shown that in the transition from the optic lobes to the central brain, due to convergence of columnar neurons onto optic glomeruli, distinct synaptic units employed in the comput...
The dopamine transporter (DAT) is a member of the solute carrier 6 (SLC6) protein family. Its physiological role is to remove dopamine from the synaptic cleft, thereby terminating neurotransmission. Several psychiatric disorders ranging from schizophrenia to attention-deficit hyperactivity disorder (ADHD) originate at least partially from DAT malfu...
Folding-defective mutants of the human dopamine transporter (DAT) cause a syndrome of infantile dystonia/Parkinsonism. Here, we provide a proof-of-principle that the folding-deficit is amenable to correction in vivo by two means, the cognate DAT ligand noribogaine and the HSP70 inhibitor, pifithrin-µ. We examined the Drosophila melanogaster mutant...
UAS-Seq/ UAS-Seq; UAS-Caps RNAi consolidation quantification.The file depicts the quantification of R8 axon consolidation following Sequoia expression induction at 12 hr APF with and without CapriciousRNAi in the background. For Sequoia expression induction without Capricious RNAi, R8 axon consolidation was quantified for 13 brains whereas 19 brain...
Sequoia expression quantification.The file depicts the average Normalised Fluorescence Intensity (NFI) of Sequoia expression analysed using anti-Sequoia antibody. The average NFI for each row of R8 cells is shown. Average NFI for Sequoia expression in each row was calculated for 60 different 3rd instar eye discs and was normalised against backgroun...
R cell axon overshooting quantification.The overshooting phenotype of R cell axons in Sequoia gain of function clones was quantified and calculated as percentage of axons overshooting. Each brain was manually analysed and total number of clone axons (GFP positive) were individually counted against number of overshooting axons. The row 1 depicts typ...
R8 axon consolidation quantification.The file depicts quantification of number of R8 axons consolidated in the superficial medulla position following induction of Sequoia expression at different developmental stages. Rows depict different developmental stages at which Sequoia expression was induced. Total number of R8 axons was counted at the stage...
List of genotypes used in this study.
The table shows detailed genotypes used in each of the experiments shown in figures and arranged to depict genotypes analysed for each representative image in the figures.
DOI:
http://dx.doi.org/10.7554/eLife.13715.022
R cell innervation quantification.The data shows quantification of total number of R8 and R7 axons innervating medulla neuropile at three different developmental stages (6/12/24 hr APF) and axons labelled by 24B10 staining at each stage. The analysis shows the number of R7 and R8 axons for each brain as well as the average numbers for each stage at...
The precise recognition of appropriate synaptic partner neurons is a critical step during neural circuit assembly. However, little is known about the developmental context in which recognition specificity is important to establish synaptic contacts. We show that in the Drosophila visual system, sequential segregation of photoreceptor afferents, ref...
Olfactory sensory neuron layers and morphology are unperturbed in the TF knock downs. Antenna from TF-IR flies stained for neuronal markers in red (Neuroglian and Elav) and counterstained with DAPI.
(TIF)
Motifs upstream all 32 analyzed ORs. Statistics related to Figure 5A. Motif location is denoted as bps upstream the translation start for each OR gene and motifs found downstream the TATA box are depicted with an asterisk.
(DOC)
TF knockdown correspond to loss of TF mRNA. In situ labeling of each TF (red) and DAPI (blue) performed on TF-IR antenna, note the tight correlation of loss of xbp1 (red) and Or92a-CD8::GFP expression (green).
(TIF)
None of the seven TFs were required for OR expression to one antenna domain or sensilla group. Regulatory matrix arranged after the five antenna domains (blue to red) and each sensilla group. Each domain is exemplified by one OR promoter fusion in green, counterstained with ELAV in red. Note that at least three of the seven TFs are required for exp...
TF-IRs phenotypes for the 32 ORs in the regulatory matrix. Statistics related to Figure 3. OR expression detected by in situ hybridizations on TF-IRs antennas and rated per animal from; 0 (loss) to 5 (control levels) and denoted as phenotype level/animals. OR expression rated above 2 was considered to be wild-type variance.
(XLS)
All tested IRs and mutants for each TF gave rise to identical phenotypes. Statistics related to Figure 1. OR expression phenotypes for two or more TF-IRs and available mutants for each gene, noted as number of animals with loss of OR expression/number of analyzed animals. Wt, wild type, denotes no loss of expression.
(DOC)
Predicted DNA motifs are bound by the identified TFs in vitro. (A) Electrophoretic mobility shift assay (EMSA) performed with radiolabeled probe containing the vertebrate Xbp1 core sequence with (+) or without (−) recombinant Xbp1. Increasing amounts (100-, 200-, 300-, 900-fold excess) of nonlabeled probe were used as cold competitors; 900-fold exc...
The mechanism that specifies olfactory sensory neurons to express only one odorant receptor (OR) from a large repertoire is critical for odor discrimination but poorly understood. Here, we describe the first comprehensive analysis of OR expression regulation in Drosophila. A systematic, RNAi-mediated knock down of most of the predicted transcriptio...
The development of the Drosophila olfactory system is a striking example of how genetic programs specify a large number of different neuron types and assemble them into functional circuits. To ensure precise odorant perception, each sensory neuron has to not only select a single olfactory receptor (OR) type out of a large genomic repertoire but als...
The segregation of axon and dendrite projections into distinct synaptic layers is a fundamental principle of nervous system organization and the structural basis for information processing in the brain. Layer-specific recognition molecules that allow projecting neurons to stabilize transient contacts and initiate synaptogenesis have been identified...
The olfactory system throughout the animal kingdom is characterized by a large number of highly specialized neuronal cell types. Olfactory receptor neurons (ORNs) in the peripheral sensory epithelium display two main differentiation features: the selective expression of a single odorant receptor out of a large genomic repertoire of receptor genes a...
The central nervous system (CNS) represents the organ with the highest structural and functional complexity. Accordingly, uncovering the mechanisms leading to cell diversity, patterning and connectivity in the CNS is one of the major challenges in developmental biology. The developing CNS of the fruitfly Drosophila melanogaster is an ideal model sy...
Mobile elements were first used as a mutagenesis tool that introduces a molecular tag in the genes of interest. This facilitated subsequent molecular cloning and eventually promoted molecular analysis of a large number of fly genes. Soon after, P-elements were modified to detect genes not only based on a mutant phenotype but rather through revealin...
The assembly of neurons into functional circuits requires a multitude of cellular recognition events. Recent work on the hypervariable Drosophila Dscam gene revealed how a vast number of cell adhesion proteins contributes to neuronal patterning.
In the olfactory system of Drosophila, 50 functional classes of sensory receptor neurons (ORNs) project in a highly organized fashion into the CNS, where they sort out from one another and converge into distinct synaptic glomeruli. We identified the transmembrane molecule Semaphorin-1a (Sema-1a) as an essential component to ensure glomerulus-specif...
In insect and vertebrate eyes, different types of color-detecting photoreceptors are randomly distributed throughout the retina. A recent study has provided important new insights into the developmental mechanisms that generate the retinal mosaic required for color vision.
In the olfactory system of Drosophila melanogaster, axons of olfactory receptor neurons (ORNs) and dendrites of second-order projection neurons typically target 1 of approximately 50 glomeruli. Dscam, an immunoglobulin superfamily protein, acts in ORNs to regulate axon targeting. Here we show that Dscam acts in projection neurons and local interneu...
The fruitfly brain learns about the olfactory world by reading the activity of about 50 distinct channels of incoming information. The receptor neurons that compose each channel have their own distinctive odour response profile governed by a specific receptor molecule. These receptor neurons form highly specific connections in the first olfactory r...
Dscam is an immunoglobulin (Ig) superfamily member that regulates axon guidance and targeting in Drosophila. Alternative splicing potentially generates 38,016 isoforms differing in their extracellular Ig and transmembrane domains. We demonstrate that Dscam mediates the sorting of axons in the developing mushroom body (MB). This correlates with the...
Drosophila olfactory receptor neurons (ORNs) elaborate a precise internal representation of the external olfactory world in the antennal lobe (AL), a structure analagous to the vertebrate olfactory bulb. ORNs expressing the same odorant receptor innervate common targets in a highly organized neuropilar structure inside the AL, the glomerulus. Durin...
Different classes of olfactory receptor neurons (ORNs) in Drosophila innervate distinct targets, or glomeruli, in the antennal lobe of the brain. Here we demonstrate that specific ORN classes require the cell surface protein Dscam (Down Syndrome Cell Adhesion Molecule) to synapse in the correct glomeruli. Dscam mutant ORNs frequently terminated in...
In the Drosophila visual system, photoreceptor neurons (R cells) extend axons towards glial cells located at the posterior edge of the eye disc. In gilgamesh (gish) mutants, glial cells invade anterior regions of the eye disc prior to R cell differentiation and R cell axons extend anteriorly along these cells. gish encodes casein kinase Igamma. gis...
In the Drosophila central nervous system (CNS) about 10% of the cells are of glial nature. A set of molecular markers has allowed unraveling a number of genes controlling glial cell fate determination as well as genes required for glial cell differentiation. Here we focus on the embryonic CNS glia and review the recent progress in the field.
Here we report the description of the Drosophila gene futsch, which encodes a protein recognized by the monoclonal antibody 22C10 that has been widely used to visualize neuronal morphology and axonal projections. The Futsch protein is 5327 amino acids in length. It localizes to the microtubule compartment of the cell and associates with microtubule...
We present evidence that Futsch, a novel protein with MAP1B homology, controls synaptic growth at the Drosophila neuromuscularjunction through the regulation of the synaptic microtubule cytoskeleton. Futsch colocalizes with microtubules and identifies cytoskeletal loops that traverse the lateral margin of select synaptic boutons. An apparent rearra...
In Drosophila, the correct formation of the segmental commissures depends on neuron-glial interactions at the midline. The VUM midline neurons extend axons along which glial cells migrate in between anterior and posterior commissures. Here, we show that the gene kette is required for the normal projection of the VUM axons and subsequently disrupts...
In the ventral nerve cord of Drosophila most axons are organized in a simple, ladder-like pattern. Two segmental commissures connect the hemisegments along the mediolateral and two longitudinal connectives connect individual neuromeres along the anterior-posterior axis. Cells located at the midline of the developing CNS first guide commissural grow...
The major axon tracts in the embryonic CNS of Drosophila are organized in a simple, ladder like pattern. Each neuromere contains two commissures which connect the contra-lateral hemi-neuromeres and two longitudinal connectives which connect the different neuromeres along the anterior-posterior axis. The formation of these axon tracts occurs in clos...
Most of the neurons of the ventral nerve cord send out long projecting axons which cross the midline. In the Drosophila central nervous system (CNS) cells of the midline give rise to neuronal and glial lineages with different functions during the establishment of the commissural pattern. Here we present evidence that beside the previously known NET...
The major axon tracts in the embryonic CNS ofDrosophila are organised in a simple, ladder-like pattern. Each neuromere contains two commissures which connect the contra-lateral sides and two longitudinal connectives which connect the different neuromeres along the anterior-posterior axis. The commissures form in close association with only few cell...
Two classes of glial cells are found in the embryonic Drosophila CNS, midline glial cells and lateral glial cells. Midline glial development is triggered by EGF-receptor signalling, whereas lateral glial development is controlled by the gcm gene. Subsequent glial cell differentiation depends partly on the pointed gene. Here we describe a novel comp...
The genetic dissection of any developmental processes requires mutagenesis protocols and the subsequent phenotypic screen
of the established mutant strains. Whereas external structures such as the Drosophila cuticle are relatively easy to score without the need of further manipulations, the analyses of internal structures such as
the nervous syste...
The first cells specified during CNS development of vertebrates and invertebrates are the cells located at the midline of the neuroepithelium. In Drosophila the development of these cells requires inductive signals from the mesoderm. Later in CNS development, the midline cells are in turn influencing the flanking neuroectoderm, contributing to the...
Each abdominal neuromere of a Drosophila embryo contains about 60 glial cells [Klämbt C, Goodman CS (1991): Glia 4:205–213; Ito et al. (1995): Roux's Arch Dev Biol, 204:284–307]. Among these, the midline and longitudinal glia are described to some detail. The midline glia are located dorsally in the nerve cord ensheathing the two segmental commissu...