@article {46606, title = {Taok2 controls behavioral response to ethanol in mice.}, journal = {Genes, Brain, and Behavior}, volume = {12}, year = {2013}, month = {2013 Feb}, pages = {87-97}, abstract = {

Despite recent advances in the understanding of ethanol{\textquoteright}s biological action, many of the molecular targets of ethanol and mechanisms behind ethanol{\textquoteright}s effect on behavior remain poorly understood. In an effort to identify novel genes, the products of which regulate behavioral responses to ethanol, we recently identified a mutation in the dtao gene that confers resistance to the locomotor stimulating effect of ethanol in Drosophila. dtao encodes a member of the Ste20 family of serine/threonine kinases implicated in MAP kinase signaling pathways. In this study, we report that conditional ablation of the mouse dtao homolog, Taok2, constitutively and specifically in the nervous system, results in strain-specific and overlapping alterations in ethanol-dependent behaviors. These data suggest a functional conservation of dtao and Taok2 in mediating ethanol{\textquoteright}s biological action and identify Taok2 as a putative candidate gene for ethanol use disorders in humans.

}, keywords = {Alcohol Drinking, Alcoholism, Animals, Behavior, Animal, Conditioning, Classical, Ethanol, Gait Ataxia, Locomotion, MAP Kinase Kinase Kinases, Mice, Mice, Inbred C57BL, Mice, Transgenic, Protein-Serine-Threonine Kinases}, issn = {1601-183X}, doi = {10.1111/j.1601-183X.2012.00834.x}, author = {Kapfhamer, D and Taylor, S and Zou, M E and Lim, J P and Kharazia, V and Heberlein, U} } @article {5480, title = {Sexual deprivation increases ethanol intake in Drosophila.}, journal = {Science}, volume = {335}, year = {2012}, month = {2012 Mar 16}, pages = {1351-5}, abstract = {

The brain{\textquoteright}s reward systems reinforce behaviors required for species survival, including sex, food consumption, and social interaction. Drugs of abuse co-opt these neural pathways, which can lead to addiction. Here, we used Drosophila melanogaster to investigate the relationship between natural and drug rewards. In males, mating increased, whereas sexual deprivation reduced, neuropeptide F (NPF) levels. Activation or inhibition of the NPF system in turn reduced or enhanced ethanol preference. These results thus link sexual experience, NPF system activity, and ethanol consumption. Artificial activation of NPF neurons was in itself rewarding and precluded the ability of ethanol to act as a reward. We propose that activity of the NPF-NPF receptor axis represents the state of the fly reward system and modifies behavior accordingly.

}, keywords = {Acetates, Addictive, Alcohol Drinking, Animal, Animals, Behavior, Cohort Studies, Conditioning (Psychology), Cues, Drosophila melanogaster, Drosophila Proteins, Ethanol, Female, Male, Neurons, Neuropeptide, Neuropeptides, Oleic Acids, Pheromones, Receptors, Reward, Sexual Behavior, TRPC Cation Channels}, issn = {1095-9203}, doi = {10.1126/science.1215932}, author = {Shohat-Ophir, G. and Kaun, K.R. and Azanchi, R. and Mohammed, H and Heberlein, U} } @article {4521, title = {Sexual experience affects ethanol intake in Drosophila through Neuropeptide F.}, journal = {Science}, volume = {335}, year = {2012}, month = {03/2012}, pages = {1351-5}, abstract = {

The brain{\textquoteright}s reward systems reinforce behaviors required for species survival, including sex, food consumption, and social interaction. Drugs of abuse co-opt these neural pathways, which can lead to addiction. Here, we used Drosophila melanogaster to investigate the relationship between natural and drug rewards. In males, mating increased, whereas sexual deprivation reduced, neuropeptide F (NPF) levels. Activation or inhibition of the NPF system in turn reduced or enhanced ethanol preference. These results thus link sexual experience, NPF system activity, and ethanol consumption. Artificial activation of NPF neurons was in itself rewarding and precluded the ability of ethanol to act as a reward. We propose that activity of the NPF{\textendash}NPF receptor axis represents the state of the fly reward system and modifies behavior accordingly.

}, doi = {10.1126/science.1215932 }, author = {Shohat-Ophir, G. and Kaun, K.R. and Azanchi, R. and Heberlein, U} } @article {46614, title = {Abnormal behavior in mice mutant for the Disc1 binding partner, Dixdc1.}, journal = {Translational Psychiatry}, volume = {1}, year = {2011}, month = {2011}, pages = {e43}, abstract = {

Disrupted-in-Schizophrenia-1 (DISC1) is a genetic susceptibility locus for major mental illness, including schizophrenia and depression. The Disc1 protein was recently shown to interact with the Wnt signaling protein, DIX domain containing 1 (Dixdc1). Both proteins participate in neural progenitor proliferation dependent on Wnt signaling, and in neural migration independently of Wnt signaling. Interestingly, their effect on neural progenitor proliferation is additive. By analogy to Disc1, mutations in Dixdc1 may lead to abnormal behavior in mice, and to schizophrenia or depression in humans. To explore this hypothesis further, we generated mice mutant at the Dixdc1 locus and analyzed their behavior. Dixdc1(-/-) mice had normal prepulse inhibition, but displayed decreased spontaneous locomotor activity, abnormal behavior in the elevated plus maze and deficits in startle reactivity. Our results suggest that Dixdc1(-/-) mice will be a useful tool to elucidate molecular pathophysiology involving Disc1 in major mental illnesses.

}, keywords = {Animals, Behavior, Animal, Epistasis, Genetic, Humans, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, 129 Strain, Mice, Mutant Strains, Mice, Transgenic, Microfilament Proteins, Nerve Tissue Proteins}, issn = {2158-3188}, doi = {10.1038/tp.2011.41}, author = {Kivim{\"a}e, S and Martin, P-M and Kapfhamer, D and Ruan, Y and Heberlein, U and Rubenstein, J L R and Cheyette, B N R} } @article {46616, title = {Lmo4 in the nucleus accumbens regulates cocaine sensitivity.}, journal = {Genes, Brain, and Behavior}, volume = {9}, year = {2010}, month = {2010 Oct}, pages = {817-24}, abstract = {

An estimated 2 million Americans use cocaine, resulting in large personal and societal costs. Discovery of the genetic factors that contribute to cocaine abuse is important for understanding this complex disease. Previously, mutations in the Drosophila LIM-only (dLmo) gene were identified because of their increased behavioral sensitivity to cocaine. Here we show that the mammalian homolog Lmo4, which is highly expressed in brain regions implicated in drug addiction, plays a similar role in cocaine-induced behaviors. Mice with a global reduction in Lmo4 levels show increased sensitivity to the locomotor stimulatory effects of cocaine upon chronic cocaine administration. This effect is reproduced with downregulation of Lmo4 in the nucleus accumbens by RNA interference. Thus, Lmo genes play conserved roles in regulating the behavioral effects of cocaine in invertebrate and mammalian models of drug addiction.

}, keywords = {Adaptor Proteins, Signal Transducing, Animals, Behavior, Animal, beta-Galactosidase, Cells, Cultured, Cloning, Molecular, Cocaine, Dendritic Spines, Dopamine Uptake Inhibitors, Gene Expression, Homeodomain Proteins, Immunohistochemistry, Lentivirus, LIM Domain Proteins, Male, Mice, Mice, Inbred C57BL, Microdissection, Motor Activity, Mutagenesis, Insertional, Nucleus Accumbens, Reverse Transcriptase Polymerase Chain Reaction, RNA, RNA Interference, Stereotaxic Techniques, Transcription Factors}, issn = {1601-183X}, doi = {10.1111/j.1601-183X.2010.00620.x}, author = {Lasek, A W and Kapfhamer, D and Kharazia, V and Gesch, J and Giorgetti, F and Heberlein, U} } @article {46626, title = {Loss of RAB-3/A in Caenorhabditis elegans and the mouse affects behavioral response to ethanol.}, journal = {Genes, Brain, and Behavior}, volume = {7}, year = {2008}, month = {2008 Aug}, pages = {669-76}, abstract = {

The mechanisms by which ethanol induces changes in behavior are not well understood. Here, we show that Caenorhabditis elegans loss-of-function mutations in the synaptic vesicle-associated RAB-3 protein and its guanosine triphosphate exchange factor AEX-3 confer resistance to the acute locomotor effects of ethanol. Similarly, mice lacking one or both copies of Rab3A are resistant to the ataxic and sedative effects of ethanol, and Rab3A haploinsufficiency increases voluntary ethanol consumption. These data suggest a conserved role of RAB-3-/RAB3A-regulated neurotransmitter release in ethanol-related behaviors.

}, keywords = {Alcohol Drinking, Alcohol-Induced Disorders, Nervous System, Animals, Ataxia, Behavior, Animal, Brain, Brain Chemistry, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Central Nervous System Depressants, Consciousness Disorders, Drug Resistance, Ethanol, Haplotypes, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, rab3 GTP-Binding Proteins, rab3A GTP-Binding Protein}, issn = {1601-183X}, doi = {10.1111/j.1601-183X.2008.00404.x}, author = {Kapfhamer, D and Bettinger, J C and Davies, A G and Eastman, C L and Smail, E A and Heberlein, U and McIntire, S L} } @article {46627, title = {Downregulation of mu opioid receptor by RNA interference in the ventral tegmental area reduces ethanol consumption in mice.}, journal = {Genes, Brain, and Behavior}, volume = {6}, year = {2007}, month = {2007 Nov}, pages = {728-35}, abstract = {

Pharmacological and genetic studies have implicated the mu opioid receptor (MOR) in the regulation of ethanol intake in animal models and humans. Non-specific antagonists of opioid receptors have been shown to affect ethanol consumption when infused directly into the ventral tegmental area (VTA) of rats. However, administration of MOR-selective antagonists into the VTA has yielded mixed results. We used RNA interference (RNAi) to specifically decrease levels of MOR messenger RNA in the VTA of mice and examined the effect on ethanol consumption in a two-bottle choice paradigm. Mice were injected in the VTA with lentivirus expressing either a small hairpin RNA (shRNA) targeting MOR or a control shRNA. One week after virus injection, mice were examined for ethanol consumption in a two-bottle choice experiment with increasing concentrations of ethanol over the course of 1 month. Expression of an shRNA targeting MOR in the VTA led to a significant reduction in ethanol consumption. These results strengthen the hypothesis that MOR in the VTA is one of the key brain substrates mediating alcohol consumption. The RNAi combined with lentiviral delivery can be used successfully in brain to effect a sustained reduction in expression of specific genes for behavioral analysis.

}, keywords = {Administration, Oral, Alcohol Drinking, Animals, Choice Behavior, Dose-Response Relationship, Drug, Down-Regulation, Ethanol, Female, Gene Transfer Techniques, Lentivirus, Mice, Mice, Inbred C57BL, Receptors, Opioid, mu, RNA Interference, RNA, Messenger, RNA, Small Interfering, Ventral Tegmental Area}, issn = {1601-1848}, doi = {10.1111/j.1601-183X.2007.00303.x}, author = {Lasek, A W and Janak, P H and He, L and Whistler, J L and Heberlein, U} } @article {46634, title = {Habituation of an odorant-induced startle response in Drosophila.}, journal = {Genes, Brain, and Behavior}, volume = {3}, year = {2004}, month = {2004 Jun}, pages = {127-37}, abstract = {

Habituation is a fundamental form of behavioral plasticity that permits organisms to ignore inconsequential stimuli. Here we describe the habituation of a locomotor response to ethanol and other odorants in Drosophila, measured by an automated high-throughput locomotor tracking system. Flies exhibit an immediate and transient startle response upon exposure to a novel odor. Surgical removal of the antennae, the fly{\textquoteright}s major olfactory organs, abolishes this startle response. With repeated discrete exposures to ethanol vapor, the startle response habituates. Habituation is reversible by a mechanical stimulus and is not due to the accumulation of ethanol in the organism, nor to non-specific mechanisms. Ablation or inactivation of the mushroom bodies, central brain structures involved in olfactory and courtship conditioning, results in decreased olfactory habituation. In addition, olfactory habituation to ethanol generalizes to odorants that activate separate olfactory receptors. Finally, habituation is impaired in rutabaga, an adenylyl cyclase mutant isolated based on a defect in olfactory associative learning. These data demonstrate that olfactory habituation operates, at least in part, through central mechanisms. This novel model of olfactory habituation in freely moving Drosophila provides a scalable method for studying the molecular and neural bases of this simple and ubiquitous form of learning.

}, keywords = {Adenylate Cyclase, Animals, Chemoreceptor Cells, Denervation, Drosophila melanogaster, Ethanol, Female, Habituation, Psychophysiologic, Learning, Male, Models, Animal, Motor Activity, Mushroom Bodies, Mutation, Odors, Physical Stimulation, Reflex, Startle, Smell}, issn = {1601-1848}, doi = {10.1111/j.1601-183x.2004.00061.x}, author = {Cho, W and Heberlein, U and Wolf, F W} } @article {46641, title = {Drosophila fasciclinII is required for the formation of odor memories and for normal sensitivity to alcohol.}, journal = {Cell}, volume = {105}, year = {2001}, month = {2001 Jun 15}, pages = {757-68}, abstract = {

Drosophila fasciclinII (fasII) mutants perform poorly after olfactory conditioning due to a defect in encoding, stabilizing, or retrieving short-term memories. Performance was rescued by inducing the expression of a normal transgene just before training and immediate testing. Induction after training but before testing failed to rescue performance, showing that Fas II does not have an exclusive role in memory retrieval processes. The stability of odor memories in fasII mutants are indistinguishable from control animals when initial performance is normalized. Like several other mutants deficient in odor learning, fasII mutants exhibit a heightened sensitivity to ethanol vapors. A combination of behavioral and genetic strategies have therefore revealed a role for Fas II in the molecular operations of encoding short-term odor memories and conferring alcohol sensitivity. The preferential expression of Fas II in the axons of mushroom body neurons furthermore suggests that short-term odor memories are formed in these neurites.

}, keywords = {Animals, Animals, Genetically Modified, Axons, Brain Chemistry, Cell Adhesion Molecules, Neuronal, Conditioning, Classical, Drosophila melanogaster, Electroshock, Ethanol, Gene Expression Regulation, Male, Memory, Short-Term, Mutation, Neurons, Odors, Smell}, issn = {0092-8674}, author = {Cheng, Y and Endo, K and Wu, K and Rodan, A R and Heberlein, U and Davis, R L} } @article {5495, title = {Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila.}, journal = {Current Biology}, volume = {10}, year = {2000}, month = {2000 Feb 24}, pages = {187-94}, abstract = {

Drugs of abuse have a common property in mammals, which is their ability to facilitate the release of the neurotransmitter and neuromodulator dopamine in specific brain regions involved in reward and motivation. This increase in synaptic dopamine levels is believed to act as a positive reinforcer and to mediate some of the acute responses to drugs. The mechanisms by which dopamine regulates acute drug responses and addiction remain unknown.

}, keywords = {Animal, Animals, Behavior, Cocaine, Dopamine, Drosophila, Ethanol, Male, Nicotine}, issn = {0960-9822}, author = {Bainton, R J and Tsai, L T and Singh, C M and Moore, M S and Neckameyer, W S and Heberlein, U} } @article {46644, title = {Early retinal development in Drosophila.}, journal = {Results and Problems in Cell Differentiation}, volume = {31}, year = {2000}, month = {2000}, pages = {37-50}, keywords = {Animals, Cell Differentiation, Drosophila melanogaster, Retina}, issn = {0080-1844}, author = {Heberlein, U and Treisman, J E} } @article {5494, title = {Functional ethanol tolerance in Drosophila.}, journal = {Neuron}, volume = {28}, year = {2000}, month = {2000 Oct}, pages = {261-71}, abstract = {

In humans, repeated alcohol consumption leads to the development of tolerance, manifested as a reduced physiological and behavioral response to a particular dose of alcohol. Here we show that adult Drosophila develop tolerance to the sedating and motor-impairing effects of ethanol with kinetics of acquisition and dissipation that mimic those seen in mammals. Importantly, this tolerance is not caused by changes in ethanol absorption or metabolism. Rather, the development of tolerance requires the functional and structural integrity of specific central brain regions. Mutants unable to synthesize the catecholamine octopamine are also impaired in their ability to develop tolerance. Taken together, these data show that Drosophila is a suitable model system in which to study the molecular and neuroanatomical bases of ethanol tolerance.

}, keywords = {Animal, Animals, Behavior, Biological, Central Nervous System, Dose-Response Relationship, Drosophila, Drug, Drug Tolerance, Ethanol, Inhalation Exposure, Male, Models, Motor Activity, Mutation, Octopamine}, issn = {0896-6273}, author = {Scholz, H and Ramond, J and Singh, C M and Heberlein, U} } @article {46643, title = {Genetic control of acute ethanol-induced behaviors in Drosophila.}, journal = {Alcoholism, Clinical and Experimental Research}, volume = {24}, year = {2000}, month = {2000 Aug}, pages = {1127-36}, abstract = {

BACKGROUND: In most organisms in which acute ethanol exposure has been studied, it leads to similar changes in behavior. Generally, low ethanol doses activate the central nervous system, whereas high doses are sedative. Sensitivity to the acute intoxicating effects of ethanol is in part under genetic control in rodents and humans, and reduced sensitivity in humans predicts the development of alcoholism (Crabbe et al., 1994; Schuckit, 1994). We have established Drosophila melanogaster as a model organism to study the mechanisms that regulate acute sensitivity to ethanol.

METHODS: We measured the effects of ethanol vapor on Drosophila locomotor behaviors by using three different assays. Horizontal locomotion was quantified in a locomotor chamber, turning behavior was assayed in narrow tubes, and ethanol-induced loss of postural control was measured in an inebriometer. Mutants with altered sensitivity to the acute effects of ethanol were generated by treatment with ethyl methane sulfonate and isolated by selection in the inebriometer. We ascertained the effects of these mutations on ethanol pharmacokinetics by measuring ethanol levels in extracts of flies at various times during and after ethanol exposure.

RESULTS: Among nearly 30,000 potentially mutant flies tested, we isolated 19 mutant strains with reduced and 4 strains with increased sensitivity to the acute effects of ethanol as measured in the inebriometer. Of these mutants, four showed changes in ethanol absorption. Two mutants, named barfly and tipsy to reflect their reduced and increased ethanol sensitivity in the inebriometer, respectively, were analyzed for locomotor behaviors. Both mutants exhibited ethanol-induced hyperactivity that was indistinguishable from wild type. However, barfly and tipsy displayed reduced and increased sensitivity to the sedative effects of ethanol, respectively. Finally, both mutants showed an increased rate of ethanol-induced turning behavior.

CONCLUSIONS: The effects of acute ethanol exposure on Drosophila locomotor behaviors are remarkably similar to those described for mammals. The analysis of mutants with altered sensitivity to ethanol revealed that the genetic pathways which regulate these responses are complex and that single genes can affect hyperactivity, turning, and sedation independently.

}, keywords = {Absorption, Animals, Behavior, Animal, Drosophila melanogaster, Drug Resistance, Ethanol, Kinetics, Motor Activity, Mutation}, issn = {0145-6008}, author = {Singh, C M and Heberlein, U} } @article {46642, title = {A screen for dominant modifiers of ro(Dom), a mutation that disrupts morphogenetic furrow progression in Drosophila, identifies groucho and hairless as regulators of atonal expression.}, journal = {Genetics}, volume = {156}, year = {2000}, month = {2000 Nov}, pages = {1203-17}, abstract = {

ro(Dom) is a dominant allele of rough (ro) that results in reduced eye size due to premature arrest in morphogenetic furrow (MF) progression. We found that the ro(Dom) stop-furrow phenotype was sensitive to the dosage of genes known to affect retinal differentiation, in particular members of the hedgehog (hh) signaling cascade. We demonstrate that ro(Dom) interferes with Hh{\textquoteright}s ability to induce the retina-specific proneural gene atonal (ato) in the MF and that normal eye size can be restored by providing excess Ato protein. We used ro(Dom) as a sensitive genetic background in which to identify mutations that affect hh signal transduction or regulation of ato expression. In addition to mutations in several unknown loci, we recovered multiple alleles of groucho (gro) and Hairless (H). Analysis of their phenotypes in somatic clones suggests that both normally act to restrict neuronal cell fate in the retina, although they control different aspects of ato{\textquoteright}s complex expression pattern.

}, keywords = {Animals, Basic Helix-Loop-Helix Transcription Factors, Crosses, Genetic, DNA-Binding Proteins, Drosophila melanogaster, Embryo, Nonmammalian, Ethyl Methanesulfonate, Female, Genes, Dominant, Genes, Insect, Helix-Loop-Helix Motifs, Male, Morphogenesis, Mutagenesis, Nerve Tissue Proteins, Phenotype, Signal Transduction}, issn = {0016-6731}, author = {Chanut, F and Luk, A and Heberlein, U} } @article {46647, title = {Dorsoventral patterning in the Drosophila retina by wingless.}, journal = {Development}, volume = {125}, year = {1998}, month = {1998 Feb}, pages = {567-77}, abstract = {

The eye imaginal disc displays dorsal-ventral (D-V) and anterior-posterior polarity prior to the onset of differentiation, which initiates at the intersection of the D-V midline with the posterior margin. As the wave of differentiation progresses anteriorly, additional asymmetry develops as ommatidial clusters rotate coordinately in opposite directions in the dorsal and ventral halves of the disc; this forms a line of mirror-image symmetry, the equator, which coincides with the D-V midline of the disc. How D-V pattern is established and how it relates to ommatidial rotation are unknown. Here we address this question by assaying the expression of various asymmetric markers under conditions that lead to ectopic differentiation, such as removal of patched or wingless function. We find that D-V patterning develops gradually and that wingless plays an important role in setting up this pattern. We show that wingless is necessary and sufficient to induce dorsal expression of the gene mirror prior to the start of differentiation and also to restrict the expression of the WR122 marker to differentiating photoreceptors near the equator. In addition, we find that manipulations in wingless expression shift the D-V axis of the disc as evidenced by changes in the expression domains of asymmetric markers, the position of the site of initiation and the equator, and the pattern of epithelial growth. Thus, Wg appears to coordinately regulate multiple events related to D-V patterning in the developing retina.

}, keywords = {Animals, Animals, Genetically Modified, Crosses, Genetic, Drosophila, Drosophila Proteins, Eye Proteins, Female, Gene Expression Regulation, Developmental, Genes, Insect, Genetic Markers, Homeodomain Proteins, Lac Operon, Larva, Male, Proto-Oncogene Proteins, Retina, Transcription Factors, Wnt1 Protein}, issn = {0950-1991}, author = {Heberlein, U and Borod, E R and Chanut, F A} } @article {5496, title = {Ethanol intoxication in Drosophila: genetic and pharmacological evidence for regulation by the cAMP signaling pathway.}, journal = {Cell}, volume = {93}, year = {1998}, month = {1998 Jun 12}, pages = {997-1007}, abstract = {

Upon exposure to ethanol, Drosophila display behaviors that are similar to ethanol intoxication in rodents and humans. Using an inebriometer to measure ethanol-induced loss of postural control, we identified cheapdate, a mutant with enhanced sensitivity to ethanol. Genetic and molecular analyses revealed that cheapdate is an allele of the memory mutant amnesiac. amnesiac has been postulated to encode a neuropeptide that activates the cAMP pathway. Consistent with this, we find that enhanced ethanol sensitivity of cheapdate can be reversed by treatment with agents that increase cAMP levels or PKA activity. Conversely, genetic or pharmacological reduction in PKA activity results in increased sensitivity to ethanol. Taken together, our results provide functional evidence for the involvement of the cAMP signal transduction pathway in the behavioral response to intoxicating levels of ethanol.

}, keywords = {Adenylate Cyclase, Alleles, Amino Acid Sequence, Animal, Animals, Base Sequence, Behavior, Cloning, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Drosophila melanogaster, Drosophila Proteins, Enzyme Activation, Enzyme Inhibitors, Ethanol, Forskolin, Genes, Genetic Complementation Test, Genetically Modified, Insect, Male, Messenger, Molecular, Molecular Sequence Data, Mutation, Neuropeptides, RNA, Signal Transduction}, issn = {0092-8674}, author = {Moore, M S and DeZazzo, J and Luk, A Y and Tully, T and Singh, C M and Heberlein, U} } @article {46648, title = {Eye development in Drosophila: formation of the eye field and control of differentiation.}, journal = {Current Topics in Developmental Biology}, volume = {39}, year = {1998}, month = {1998}, pages = {119-58}, keywords = {Animals, Cell Differentiation, Drosophila, Eye, Gene Expression Regulation, Developmental, Larva, Morphogenesis, Mutation, Visual Fields}, issn = {0070-2153}, author = {Treisman, J E and Heberlein, U} } @article {46646, title = {Mutual regulation of decapentaplegic and hedgehog during the initiation of differentiation in the Drosophila retina.}, journal = {Devopemental Biology}, volume = {197}, year = {1998}, month = {1998 May 15}, pages = {187-97}, abstract = {

Neuronal differentiation in the Drosophila retinal primordium, the eye imaginal disc, begins at the posterior tip of the disc and progresses anteriorly as a wave. The morphogenetic furrow (MF) marks the boundary between undifferentiated anterior cells and differentiating posterior cells. Anterior progression of differentiation is driven by Hedgehog, synthesized by cells located posterior to the MF. We report here that hedgehog (hh), which is expressed prior to the start of differentiation along the disc{\textquoteright}s posterior margin, also plays a crucial role in the initiation of differentiation. Using a temperature-sensitive allele we show that hh is normally required at the posterior margin to maintain the expression of decapentaplegic (dpp) and of the proneural gene atonal. In addition, we find that ectopic differentiation driven by ectopic dpp expression or loss of wingless function requires hh. Consistent with this is our observation that ectopic dpp induces the expression of hh along the anterior margin even in the absence of differentiation. Taken together, these data reveal a novel positive regulatory loop between dpp and hh that is essential for the initiation of differentiation in the eye disc.

}, keywords = {Animals, Animals, Genetically Modified, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, DNA-Binding Proteins, Drosophila, Drosophila Proteins, Female, Gene Expression Regulation, Developmental, Genes, Insect, Hedgehog Proteins, Immunohistochemistry, Insect Proteins, Larva, Male, Nerve Tissue Proteins, Neurons, Retina}, issn = {0012-1606}, doi = {10.1006/dbio.1998.8888}, author = {Borod, E R and Heberlein, U} } @article {46645, title = {Y do we drink?}, journal = {Cell}, volume = {95}, year = {1998}, month = {1998 Dec 11}, pages = {733-5}, keywords = {Alcohol Drinking, Alcoholic Intoxication, Animals, Ethanol, Feeding Behavior, Humans, Mice, Mice, Mutant Strains, Neuropeptide Y, Rats}, issn = {0092-8674}, author = {Tecott, L H and Heberlein, U} } @article {46649, title = {eyelid antagonizes wingless signaling during Drosophila development and has homology to the Bright family of DNA-binding proteins.}, journal = {Genes \& Development}, volume = {11}, year = {1997}, month = {1997 Aug 1}, pages = {1949-62}, abstract = {

In Drosophila, pattern formation at multiple stages of embryonic and imaginal development depends on the same intercellular signaling pathways. We have identified a novel gene, eyelid (eld), which is required for embryonic segmentation, development of the notum and wing margin, and photoreceptor differentiation. In these tissues, eld mutations have effects opposite to those caused by wingless (wg) mutations. eld encodes a widely expressed nuclear protein with a region homologous to a novel family of DNA-binding domains. Based on this homology and on the phenotypic analysis, we suggest that Eld could act as a transcription factor antagonistic to the Wg pathway.

}, keywords = {Amino Acid Sequence, Animals, Body Patterning, Cell Differentiation, Cloning, Molecular, DNA-Binding Proteins, Drosophila, Drosophila Proteins, Gene Expression Regulation, Developmental, Genes, Insect, Molecular Sequence Data, Mutation, Phenotype, Photoreceptor Cells, Invertebrate, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Restriction Mapping, Sequence Homology, Amino Acid, Signal Transduction, Trans-Activators, Transcription Factors, Wing, Wnt1 Protein}, issn = {0890-9369}, author = {Treisman, J E and Luk, A and Rubin, G M and Heberlein, U} } @article {46650, title = {Retinal morphogenesis in Drosophila: hints from an eye-specific decapentaplegic allele.}, journal = {Developmental Genetics}, volume = {20}, year = {1997}, month = {1997}, pages = {197-207}, abstract = {

Decapentaplegic (dpp) regulates many aspects of imaginal disc growth and patterning in Drosophila. We have analyzed the phenotype of an eye-specific dpp allele, dppblk, which causes a reduction in the size of the retina due to a loss of ventral ommatidia. Prior to the onset of differentiation, dppblk eye discs are normal regarding size, shape, and ability to express dorsal and ventral markers. However, expression of a dpp-lacZ reporter is reduced at the ventral margin. Additional dorsoventral asymmetry appears during retinal differentiation: the morphogenetic furrow (MF) initiates normally at the posterior tip of the disc, but fails to propagate into the ventral epithelium. This defect can be rescued by increasing dpp expression along the ventral margin by local removal of patched function. We propose that the primary defect in dppblk is an inability to activate dpp expression properly at the ventral margin. This has two consequences: it prevents initiation from the ventral margin, and it renders the ventral epithelium unresponsive to differentiation signals emanating from the MF.

}, keywords = {Animals, Drosophila, Drosophila Proteins, Insect Proteins, Morphogenesis, Mutation, Phenotype, Photoreceptor Cells, Invertebrate, Retina}, issn = {0192-253X}, doi = {10.1002/(SICI)1520-6408(1997)20:3<197::AID-DVG3>3.0.CO;2-2}, author = {Chanut, F and Heberlein, U} } @article {46651, title = {Role of decapentaplegic in initiation and progression of the morphogenetic furrow in the developing Drosophila retina.}, journal = {Development}, volume = {124}, year = {1997}, month = {1997 Jan}, pages = {559-67}, abstract = {

Morphogenesis in the Drosophila retina initiates at the posterior margin of the eye imaginal disc by an unknown mechanism. Upon initiation, a wave of differentiation, its forward edge marked by the morphogenetic furrow (MF), proceeds anteriorly across the disc. Progression of the MF is driven by hedgehog (hh), expressed by differentiating photoreceptor cells. The TGF-beta homolog encoded by decapentaplegic (dpp) is expressed at the disc{\textquoteright}s posterior margin prior to initiation and in the furrow, under the control of hh, during MF progression. While dpp has been implicated in eye disc growth and morphogenesis, its precise role in retinal differentiation has not been determined. To address the role of dpp in initiation and progression of retinal differentiation we analyzed the consequences of reduced and increased dpp function during eye development. We find that dpp is not only required for normal MF initiation, but is sufficient to induce ectopic initiation of differentiation. Inappropriate initiation is normally inhibited by wingless (wg). Loss of dpp function is accompanied by expansion of wg expression, while increased dpp function leads to loss of wg transcription. In addition, dpp is required to maintain, and sufficient to induce, its own expression along the disc{\textquoteright}s margins. We postulate that dpp autoregulation and dpp-mediated inhibition of wg expression are required for the coordinated regulation of furrow initiation and progression. Finally, we show that in the later stages of retinal differentiation, reduction of dpp function leads to an arrest in MF progression.

}, keywords = {Animals, Cell Differentiation, Chromosome Mapping, Drosophila, Drosophila Proteins, Embryo, Nonmammalian, Embryonic Induction, Gene Expression Regulation, Developmental, Genes, Insect, Hedgehog Proteins, Insect Proteins, Morphogenesis, Proto-Oncogene Proteins, Retina, Transcription, Genetic, Wnt1 Protein}, issn = {0950-1991}, author = {Chanut, F and Heberlein, U} } @article {46654, title = {Growth and differentiation in the Drosophila eye coordinated by hedgehog.}, journal = {Nature}, volume = {373}, year = {1995}, month = {1995 Feb 23}, pages = {709-11}, abstract = {

Differentiation of the Drosophila retina is asynchronous: it starts at the posterior margin of the eye imaginal disc and progresses anteriorly over two days. During this time the disc continues to grow, increasing in size by approximately eightfold. An indentation in the epithelium, the morphogenetic furrow, marks the front edge of the differentiation wave. Anterior progression of the furrow is thought to be driven by signals emanating from differentiating photoreceptor cells in the posterior eye disc. A good candidate for such a signal is the product of the hedgehog (hh) gene; it is expressed, and presumably secreted, by differentiating photoreceptors and its function is required for continued furrow movement. Here we show that ectopic expression of hedgehog sets in motion ectopic furrows in the anterior eye disc. In addition to changes in cell shape, these ectopic furrows are associated with a tightly orchestrated series of events, including proliferation, cell cycle synchronization and pattern formation, that parallel normal furrow progression. We propose that the morphogenetic furrow coincides with a transient boundary that coordinates growth and differentiation of the eye disc, and that hedgehog is necessary and sufficient to propagate this boundary across the epithelium.

}, keywords = {Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Cycle, Cell Cycle Proteins, DNA-Binding Proteins, Drosophila, Drosophila Proteins, Embryonic Induction, Eye, Hedgehog Proteins, Helix-Loop-Helix Motifs, Insect Hormones, Insect Proteins, Nerve Tissue Proteins, Phosphoprotein Phosphatases, Protein Tyrosine Phosphatases, Proteins, Repressor Proteins, Signal Transduction, Transcription Factors}, issn = {0028-0836}, doi = {10.1038/373709a0}, author = {Heberlein, U and Singh, C M and Luk, A Y and Donohoe, T J} } @article {46653, title = {Mechanisms of Drosophila retinal morphogenesis: the virtues of being progressive.}, journal = {Cell}, volume = {81}, year = {1995}, month = {1995 Jun 30}, pages = {987-90}, keywords = {Animals, Cell Differentiation, Drosophila, Morphogenesis, Retina, Signal Transduction}, issn = {0092-8674}, author = {Heberlein, U and Moses, K} } @article {46652, title = {Role of the morphogenetic furrow in establishing polarity in the Drosophila eye.}, journal = {Development}, volume = {121}, year = {1995}, month = {1995 Dec}, pages = {4085-94}, abstract = {

The Drosophila retina is a crystalline array of 800 ommatidia whose organization and assembly suggest polarization of the retinal epithelium along anteroposterior and dorsoventral axes. The retina develops by a stepwise process following the posterior-to-anterior progression of the morphogenetic furrow across the eye disc. Ectopic expression of hedgehog or local removal of patched function generates ectopic furrows that can progress in any direction across the disc leaving in their wake differentiating fields of ectopic ommatidia. We have studied the effect of these ectopic furrows on the polarity of ommatidial assembly and rotation. We find that the anteroposterior asymmetry of ommatidial assembly parallels the progression of ectopic furrows, regardless of their direction. In addition, ommatidia developing behind ectopic furrows rotate coordinately, forming equators in various regions of the disc. Interestingly, the expression of a marker normally restricted to the equator is induced in ectopic ommatidial fields. Ectopic equators are stable as they persist to adulthood, where they can coexist with the normal equator. Our results suggest that ectopic furrows can impart polarity to the disc epithelium, regarding the direction of both assembly and rotation of ommatidia. We propose that these processes are polarized as a consequence of furrow propagation, while more global determinants of dorsoventral and anteroposterior polarity may act less directly by determining the site of furrow initiation.

}, keywords = {Animals, Drosophila, Drosophila Proteins, Eye, Gene Expression, Genes, Insect, Hedgehog Proteins, Immunohistochemistry, Insect Hormones, Membrane Proteins, Models, Biological, Morphogenesis, Proteins, Receptors, Cell Surface, Retina}, issn = {0950-1991}, author = {Chanut, F and Heberlein, U} } @article {964, title = {The TGF beta homolog dpp and the segment polarity gene hedgehog are required for propagation of a morphogenetic wave in the Drosophila retina.}, journal = {Cell}, volume = {75}, year = {1993}, month = {1993 Dec 3}, pages = {913-26}, abstract = {

Development of the Drosophila retina occurs asynchronously; differentiation, its front marked by the morphogenetic furrow, progresses across the eye disc epithelium over a 2 day period. We have investigated the mechanism by which this front advances, and our results suggest that developing retinal cells drive the progression of morphogenesis utilizing the products of the hedgehog (hh) and decapentaplegic (dpp) genes. Analysis of hh and dpp genetic mosaics indicates that the products of these genes act as diffusible signals in this process. Expression of dpp in the morphogenetic furrow is closely correlated with the progression of the furrow under a variety of conditions. We show that hh, synthesized by differentiating cells, induces the expression of dpp, which appears to be a primary mediator of furrow movement.

}, keywords = {Animals, Cell Differentiation, Drosophila melanogaster, Drosophila Proteins, Eye, Gene Expression, Genes, Hedgehog Proteins, Insect, Insect Hormones, Invertebrate, Messenger, Morphogenesis, Mosaicism, Photoreceptor Cells, Proteins, Retina, RNA, Transforming Growth Factor beta}, issn = {0092-8674}, doi = {10.1186/gb-2007-8-7-r145}, author = {Heberlein, U and Wolff, T and Rubin, G M} } @article {969, title = {The homeo domain protein rough is expressed in a subset of cells in the developing Drosophila eye where it can specify photoreceptor cell subtype.}, journal = {Genes \& Development}, volume = {4}, year = {1990}, month = {1990 May}, pages = {712-27}, abstract = {

The Drosophila homeo box gene rough is required in photoreceptor cells R2 and R5 for normal eye development. We show here that rough protein expression is limited to a subset of cells in the developing retina where it is transiently expressed for 30-60 hr. The rough protein is first expressed broadly in the morphogenetic furrow but is rapidly restricted to the R2, R3, R4, and R5 precursor cells. Ubiquitous expression of rough under the control of the hsp70 promoter in third-instar larvae suppresses the initial steps of ommatidial assembly. Structures derived from other imaginal discs are not affected. Ectopic expression of rough in the R7 precursor, through the use of the sevenless promoter, causes this cell to develop into an R1-6 photoreceptor subtype; however, this cell still requires sevenless function for its neural differentiation. Taken together with previous analyses of the rough mutant phenotype, these results suggest that the normal role of rough is to establish the unique cell identity of photoreceptors R2 and R5.

}, keywords = {Animals, Base Sequence, Cell Cycle Proteins, DNA-Binding Proteins, Drosophila melanogaster, Drosophila Proteins, Eye, Gene Expression, Genes, Genetic, Heat-Shock Proteins, Homeobox, Hot Temperature, Microtubule-Associated Proteins, Molecular Sequence Data, Morphogenesis, Phenotype, Photoreceptor Cells, Promoter Regions, Transcription Factors}, issn = {0890-9369}, doi = {10.1186/gb-2007-8-7-r145}, author = {Kimmel, B E and Heberlein, U and Rubin, G M} }