A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects.

Notch signaling is a conserved pathway that converts extracellular receptor-ligand interactions into changes in gene expression via a single transcription factor (CBF1/RBPJ in mammals; Su(H) in Drosophila). In humans, RBPJ variants have been linked to Adams-Oliver syndrome (AOS), a rare autosomal dominant disorder characterized by scalp, cranium, and limb defects. Here, we found that a previously described Drosophila Su(H) allele encodes a missense mutation that alters an analogous residue found in an AOS-associated RBPJ variant.

Ca-Activated K Channels Reduce Network Excitability, Improving Adaptability and Energetics for Transmitting and Perceiving Sensory Information.

Ca-activated K channels (BK and SK) are ubiquitous in synaptic circuits, but their role in network adaptation and sensory perception remains largely unknown. Using electrophysiological and behavioral assays and biophysical modeling, we discover how visual information transfer in mutants lacking the BK channel ( ), SK channel ( ), or both ( ;; ) is shaped in the female fruit fly () R1-R6 photoreceptor-LMC circuits (R-LMC-R system) through synaptic feedforward-feedback interactions and reduced R1-R6 and K conductances. This homeostatic compensation is specific for each mutant, leading to distinctive adaptive dynamics.

Interallelic Transcriptional Enhancement as an in Vivo Measure of Transvection in Drosophila melanogaster.

Transvection-pairing-dependent interallelic regulation resulting from enhancer action in trans-occurs throughout the Drosophila melanogaster genome, likely as a result of the extensive somatic homolog pairing seen in Dipteran species. Recent studies of transvection in Drosophila have demonstrated important qualitative differences between enhancer action in cis vs. in trans, as well as a modest synergistic effect of cis- and trans-acting enhancers on total tissue transcript levels at a given locus.

Measurement of the target-normal single-spin asymmetry in deep-inelastic scattering from the reaction (3)He(↑)(e,e')X.

We report the first measurement of the target-normal single-spin asymmetry in deep-inelastic scattering from the inclusive reaction 3)He(↑)(e,e')X on a polarized (3)He gas target. Assuming time-reversal invariance, this asymmetry is strictly zero in the Born approximation but can be nonzero if two-photon-exchange contributions are included. The experiment, conducted at Jefferson Lab using a 5.

Phosphatidic acid phospholipase A1 mediates ER-Golgi transit of a family of G protein-coupled receptors.

The coat protein II (COPII)-coated vesicular system transports newly synthesized secretory and membrane proteins from the endoplasmic reticulum (ER) to the Golgi complex. Recruitment of cargo into COPII vesicles requires an interaction of COPII proteins either with the cargo molecules directly or with cargo receptors for anterograde trafficking. We show that cytosolic phosphatidic acid phospholipase A1 (PAPLA1) interacts with COPII protein family members and is required for the transport of Rh1 (rhodopsin 1), an N-glycosylated G protein-coupled receptor (GPCR), from the ER to the Golgi complex.

Reversible symptoms and clearance of mutant prion protein in an inducible model of a genetic prion disease in Drosophila melanogaster.

Prion diseases are progressive disorders that affect the central nervous system leading to memory loss, personality changes, ataxia and neurodegeneration. In humans, these disorders include Creutzfeldt-Jakob disease, kuru and Gerstmann-Straüssler-Scheinker (GSS) syndrome, the latter being a dominantly inherited prion disease associated with missense mutations in the gene that codes for the prion protein. The exact mechanism by which mutant prion proteins affect the central nervous system and cause neurological disease is not well understood.

Roles of the Drosophila SK channel (dSK) in courtship memory.

A role for SK channels in synaptic plasticity has been very well-characterized. However, in the absence of simple genetic animal models, their role in behavioral memory remains elusive. Here, we take advantage of Drosophila melanogaster with its single SK gene (dSK) and well-established courtship memory assay to investigate the contribution of this channel to memory.

Cathepsin proteases mediate photoreceptor cell degeneration in Drosophila.

Endocytosis-mediated cell death is a form of degeneration displayed in several Drosophila mutants. This form of degeneration is displayed in several Drosophila mutant lines including flies lacking the eye-specific PLC (norpA). The cell death pathway is initiated by the stabilization of complexes between rhodopsin and arrestin which undergo massive endocytosis into the cell body.

Beam-target double-spin asymmetry A{LT} in charged pion production from deep inelastic scattering on a transversely polarized {3}He target at 1.4

We report the first measurement of the double-spin asymmetry A{LT} for charged pion electroproduction in semi-inclusive deep-inelastic electron scattering on a transversely polarized {3}He target. The kinematics focused on the valence quark region, 0.16 View Article and Find Full Text PDF

Alternative pathway of cell death in Drosophila mediated by NF-κB transcription factor Relish.

Photoreceptor cell death accompanying many retinal degenerative disorders results in irreversible loss of vision in humans. However, the precise molecular pathway that executes cell death is not known. Our results from a Drosophila model of retinal degeneration corroborate previously reported findings that the developmental apoptotic pathway is not involved in photoreceptor cell demise.

Characterization of two dominant alleles of the major rhodopsin-encoding gene ninaE in Drosophila.

Purpose: In this study we investigated the biochemical and cell biologic characteristics of flies expressing two novel dominant alleles of the major rhodopsin encoding gene neither inactivation nor afterpotential E (ninaE) in a heterozygous background.

Methods: Presence of the deep pseudopupil in flies was assayed 5 days post eclosion. For structural analysis, 1-μm-retinal cross sections were obtained from fixed and resin-embedded Drosophila heads.

The Drosophila SK channel (dSK) contributes to photoreceptor performance by mediating sensitivity control at the first visual network.

The contribution of the SK (small-conductance calcium-activated potassium) channel to neuronal functions in complex circuits underlying sensory processing and behavior is largely unknown in the absence of suitable animal models. Here, we generated a Drosophila line that lacks the single highly conserved SK gene in its genome (dSK). In R1-R6 photoreceptors, dSK encodes a slow Ca²⁺-activated K(+) current similar to its mammalian counterparts.

Single spin asymmetries in charged pion production from semi-inclusive deep inelastic scattering on a transversely polarized 3He Target at Q2 = 1.4-2.7 GeV2.

We report the first measurement of target single spin asymmetries in the semi-inclusive (3)He(e,e'π(±))X reaction on a transversely polarized target. The experiment, conducted at Jefferson Lab using a 5.9 GeV electron beam, covers a range of 0.

Measurements of the electric form factor of the neutron up to Q2=3.4 GeV2 using the reaction 3He(e,e'n)pp.

The electric form factor of the neutron was determined from studies of the reaction 3He(e,e'n)pp in quasielastic kinematics in Hall A at Jefferson Lab. Longitudinally polarized electrons were scattered off a polarized target in which the nuclear polarization was oriented perpendicular to the momentum transfer. The scattered electrons were detected in a magnetic spectrometer in coincidence with neutrons that were registered in a large-solid-angle detector.

Whole-cell patch-clamp analysis of adult Drosophila photoreceptors.

Adult Drosophila have a compound eye composed of approximately 750 repeating units, called ommatidia, packed together to form the retina. Each ommatidium is a precise arrangement of 19 cells: eight photoreceptors (primary sensory neurons) and 11 accessory cells. Analysis of visual physiology in Drosophila photoreceptors has been central to understanding a number of important areas of modern biology including the G-protein-coupled receptor cycle, phosphoinositide signaling, and calcium signaling.

Preparation of dissociated ommatidia from Drosophila.

Adult Drosophila have a compound eye composed of approximately 750 repeating units, called ommatidia, packed together to form the retina. Each ommatidium is a precise arrangement of 19 cells: eight photoreceptors (primary sensory neurons) and 11 accessory cells. Analysis of visual physiology in Drosophila photoreceptors has been central to understanding a number of important areas of modern biology, including the G-protein-coupled receptor cycle, phosphoinositide signaling, and calcium signaling.

Electroretinogram recordings of Drosophila.

Analysis of visual physiology in Drosophila photoreceptors has been central to understanding a number of important areas of modern biology, including the G-protein-coupled receptor cycle, phosphoinositide signaling, and calcium signaling. Analysis of photoreceptor performance and synaptic transmission are areas of neurobiology that have been studied using Drosophila photoreceptors as a model system. Electrophysiological analysis of responses to light is a powerful tool for characterizing and understanding visual transduction in Drosophila photoreceptors, and electroretinograms (ERGs) have long been used as a physiological assay in the Drosophila visual system.

Ceramide kinase regulates phospholipase C and phosphatidylinositol 4, 5, bisphosphate in phototransduction.

Phosphoinositide-specific phospholipase C (PLC) is a central effector for many biological responses regulated by G-protein-coupled receptors including Drosophila phototransduction where light sensitive channels are activated downstream of NORPA, a PLCbeta homolog. Here we show that the sphingolipid biosynthetic enzyme, ceramide kinase, is a novel regulator of PLC signaling and photoreceptor homeostasis. A mutation in ceramide kinase specifically leads to proteolysis of NORPA, consequent loss of PLC activity, and failure in light signal transduction.

Cell-autonomous requirement for DNaseII in nonapoptotic cell death.

DNA fragmentation is a critical component of apoptosis but it has not been characterized in nonapoptotic forms of cell death, such as necrosis and autophagic cell death. In mammalian apoptosis, caspase-activated DNase cleaves DNA into nucleosomal fragments in dying cells, and subsequently DNase II, an acid nuclease, completes the DNA degradation but acts non-cell autonomously within lysosomes of engulfing cells. Here we examine the requirement for DNases during two examples of programmed cell death (PCD) that occurs in the Drosophila melanogaster ovary, starvation-induced death of mid-stage egg chambers and developmental nurse cell death in late oogenesis.

Accumulation of rhodopsin in late endosomes triggers photoreceptor cell degeneration.

Progressive retinal degeneration is the underlying feature of many human retinal dystrophies. Previous work using Drosophila as a model system and analysis of specific mutations in human rhodopsin have uncovered a connection between rhodopsin endocytosis and retinal degeneration. In these mutants, rhodopsin and its regulatory protein arrestin form stable complexes, and endocytosis of these complexes causes photoreceptor cell death.

New insights into Drosophila vision.

Studies of the Drosophila visual system have provided valuable insights into the function and regulation of phototransduction signaling pathways. Much of this work has stemmed from or relied upon the genetic tools offered by the Drosophila system. In this issue of Neuron, Wang and colleagues and Acharya and colleagues have further exploited the Drosophila genetic system to characterize two new phototransduction players.

The role of carcinine in signaling at the Drosophila photoreceptor synapse.

The Drosophila melanogaster photoreceptor cell has long served as a model system for researchers focusing on how animal sensory neurons receive information from their surroundings and translate this information into chemical and electrical messages. Electroretinograph (ERG) analysis of Drosophila mutants has helped to elucidate some of the genes involved in the visual transduction pathway downstream of the photoreceptor cell, and it is now clear that photoreceptor cell signaling is dependent upon the proper release and recycling of the neurotransmitter histamine. While the neurotransmitter transporters responsible for clearing histamine, and its metabolite carcinine, from the synaptic cleft have remained unknown, a strong candidate for a transporter of either substrate is the uncharacterized inebriated protein.

Accelerated accumulation of misfolded prion protein and spongiform degeneration in a Drosophila model of Gerstmann-Sträussler-Scheinker syndrome.

Prion diseases are CNS disorders that can occur in sporadic, infectious, and inherited forms. Although all forms of prion disease are associated with the accumulation of pathogenic conformers of the prion protein, collectively termed PrP(Sc), the mechanisms by which PrP(Sc) molecules form and cause neuronal degeneration are unknown. Using the bipartite galactosidase-4-upstream activating sequence expression system, we generated transgenic Drosophila melanogaster heterologously expressing either wild-type (WT) or mutant, disease-associated (P101L) mouse PrP molecules in cholinergic neurons.

An essential role for endocytosis of rhodopsin through interaction of visual arrestin with the AP-2 adaptor.

Previously, we have identified a class of retinal degeneration mutants in Drosophila in which the normally transient interaction between arrestin2 (Arr2) and rhodopsin is stabilized and the complexes are rapidly internalized into the cell body by receptor-mediated endocytosis. The accumulation of protein complexes in the cytoplasm eventually results in photoreceptor cell death. We now show that the endocytic adapter protein AP-2 is essential for rhodopsin endocytosis through an Arr2-AP-2beta interaction, and mutations in Arr2 that disrupt its interaction with the beta subunit of AP-2 prevent endocytosis-induced retinal degeneration.

Molecular cloning of the pawn locus from Drosophila melanogaster.

Alleles of pawn have numerous morphological phenotypes, including dark deposits on the eye, truncated bristles, and semilethality. The gene encoding the pawn locus was cloned. The Pawn protein is predicted to be a large cell adhesion molecule with a single transmembrane domain, a short cytoplasmic tail and two extracellular epidermal growth factor (EGF)-like repeats.