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94 Publications

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    08/01/00 | Genetic control of acute ethanol-induced behaviors in Drosophila.
    Singh CM, Heberlein U
    Alcoholism, Clinical and Experimental Research. 2000 Aug;24(8):1127-36

    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.

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    02/24/00 | Dopamine modulates acute responses to cocaine, nicotine and ethanol in Drosophila.
    Bainton RJ, Tsai LT, Singh CM, Moore MS, Neckameyer WS, Heberlein U
    Current Biology. 2000 Feb 24;10(4):187-94

    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.

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    01/01/00 | Early retinal development in Drosophila.
    Heberlein U, Treisman JE
    Results and Problems in Cell Differentiation. 2000;31:37-50
    12/11/99 | Y do we drink?
    Tecott LH, Heberlein U
    Cell. 1998 Dec 11;95(6):733-5
    06/12/98 | Ethanol intoxication in Drosophila: genetic and pharmacological evidence for regulation by the cAMP signaling pathway.
    Moore MS, DeZazzo J, Luk AY, Tully T, Singh CM, Heberlein U
    Cell. 1998 Jun 12;93(6):997-1007

    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.

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    05/15/98 | Mutual regulation of decapentaplegic and hedgehog during the initiation of differentiation in the Drosophila retina.
    Borod ER, Heberlein U
    Devopemental Biology. 1998 May 15;197(2):187-97. doi: 10.1006/dbio.1998.8888

    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'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.

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    02/01/98 | Dorsoventral patterning in the Drosophila retina by wingless.
    Heberlein U, Borod ER, Chanut FA
    Development. 1998 Feb;125(4):567-77

    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.

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    01/01/98 | Eye development in Drosophila: formation of the eye field and control of differentiation.
    Treisman JE, Heberlein U
    Current Topics in Developmental Biology. 1998;39:119-58
    08/01/97 | eyelid antagonizes wingless signaling during Drosophila development and has homology to the Bright family of DNA-binding proteins.
    Treisman JE, Luk A, Rubin GM, Heberlein U
    Genes & Development. 1997 Aug 1;11(15):1949-62

    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.

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    01/01/97 | Retinal morphogenesis in Drosophila: hints from an eye-specific decapentaplegic allele.
    Chanut F, Heberlein U
    Developmental Genetics. 1997;20(3):197-207. doi: 10.1002/(SICI)1520-6408(1997)20:3<197::AID-DVG3>3.0.CO;2-2

    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.

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