Multiple Amidated Neuropeptides Are Required for Normal Circadian Locomotor Rhythms in<i>Drosophila</i>

Taghert, Paul H.; Hewes, Randall S.; Park, Jae H.; O’Brien, Martha A.; Han, Mei; Peck, Molly E.

doi:10.1523/jneurosci.21-17-06673.2001

Cited by 124 publications

(120 citation statements)

References 37 publications

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“…We wondered whether overexpression of NPF could cause increased alcohol sensitivity. An enhancer-trap gal4 line (386Y-gal4) was chosen because it was previously shown to drive reporter expression in brain cells, including peptidergic neurons (26). Transgenic flies containing UAS-npf driven by 386Y-gal4 showed strong ectopic expression of NPF in the adult brain (data not shown) and were tested for alcohol resistance.…”

Section: Resultsmentioning

confidence: 99%

Drosophila neuropeptide F and its receptor, NPFR1, define a signaling pathway that acutely modulates alcohol sensitivity

Wen

Parrish²,

Xu³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

178

191

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Alcohol is likely to affect neurons nonselectively, and the understanding of its action in the CNS requires elucidation of underlying neuronal circuits and associated cellular processes. We have identified a Drosophila signaling system, comprising neurons expressing neuropeptide F (NPF, a homolog of mammalian neuropeptide Y) and its receptor, NPFR1, that acutely mediates sensitivity to ethanol sedation. Flies deficient in NPF͞NPFR1 signaling showed decreased alcohol sensitivity, whereas those overexpressing NPF exhibited the opposite phenotype. Furthermore, controlled functional disruption of NPF or NPFR1 neurons in adults rapidly confers resistance to ethanol sedation. Finally, the NPF͞NPFR1 system selectively mediates sedation by ethanol vapor but not diethyl ether, indicating that the observed NPF͞NPFR1 activity reflects a specialized response to alcohol sedation rather than a general response to intoxication by sedative agents. Together, our results provide the molecular and neural basis for the strikingly similar alcohol-responsive behaviors between flies and mammals.acute ethanol response ͉ neuropeptide Y ͉ neuropeptide F receptor A lcohol, a widely abused drug, impacts the functioning of the CNS in diverse animals. The behavioral responses to acute alcohol exposure are remarkably similar among humans, rodents, and even fruit flies. Alcohol induces an excitatory state at lower concentrations but exerts a sedative effect at higher doses (1, 2). The current knowledge about how this drug impacts the functioning of the CNS is rather limited. Ethanol is highly soluble in both water and lipids, and is likely to act on neurons in a nonselective manner. However, the sensitivity of neurons in different neural circuits to this drug may vary greatly (3). Thus, elucidation of neuronal circuits and underlying molecular mechanisms essential for alcohol sensitivity is a prerequisite for understanding how alcohol interferes with the functioning of the CNS.Neuropeptides are a group of chemically diverse signal molecules implicated in modulating a broad spectrum of physiological processes and behaviors (4). Mammalian neuropeptide Y (NPY) is a 36 aa neuromodulator present abundantly in many regions of the CNS, and acts thorough a number of Y receptor subtypes (5). Mice lacking NPY or Y1 displayed increased ethanol consumption and resistance to alcohol sedation, whereas animals overexpressing NPY showed opposite behavioral phenotypes (6, 7). These results provide genetic evidence of a critical role of the NPY signaling system in acute ethanol response. However, the elucidation of the physiological role of the NPY system and the action sites has been difficult largely because of the complexity of mammalian models.NPY family molecules have been found in diverse organisms (8-10). Neuropeptide F (NPF) is the sole member of the NPY family in the Drosophila genome, and its action is mediated by G protein-coupled seven-transmembrane receptors related to mammalian NPY receptors (11). Both NPY and NPF are present prominently, although...

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Section: Resultsmentioning

confidence: 99%

Drosophila neuropeptide F and its receptor, NPFR1, define a signaling pathway that acutely modulates alcohol sensitivity

Wen

Parrish²,

Xu³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

178

191

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“…How the circadian clock controls output behaviors is not known. A neuropeptide, pigment-dispersing factor (pdf ), is necessary for coupling the central clock mechanism to behavioral rhythmicity and is hypothesized to represent the transmitter output of the primary pacemaker neurons (19,20). The pdf gene, however, is not expressed rhythmically (21).…”

Section: Discussionmentioning

confidence: 99%

Influence of the period -dependent circadian clock on diurnal, circadian, and aperiodic gene expression in Drosophila melanogaster

Lin

Han

Shimada

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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173

179

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We measured daily gene expression in heads of control and period mutant Drosophila by using oligonucleotide microarrays. In control flies, 72 genes showed diurnal rhythms in light-dark cycles; 22 of these also oscillated in free-running conditions. The period gene significantly influenced the expression levels of over 600 nonoscillating transcripts. Expression levels of several hundred genes also differed significantly between control flies kept in light-dark versus constant darkness but differed minimally between per 01 flies kept in the same two conditions. Thus, the period-dependent circadian clock regulates only a limited set of rhythmically expressed transcripts. Unexpectedly, period regulates basal and light-regulated gene expression to a very broad extent.F orward genetic screens in Drosophila melanogaster have identified at least eight genes [period (per), timeless (tim), cycle (cyc), clock (Clk), vrille (vri), doubletime, cryptochrome (cry), and shaggy] necessary for the normal functioning of the circadian time-keeping system. Null mutations in most of these genes render flies behaviorally arrhythmic in constant conditions, but they otherwise have minimal morphologic phenotype (1). A model for the mechanism by which specific gene products give rise to a stable clock mechanism has been formulated over the past 10 years (2, 3). These clock genes appear to function in a time-delayed transcription-translation feedback loop. A rhythmically expressed subset of the core clock genes (per, tim, and Clk) and a nonrhythmically expressed core clock gene (cyc) are thought to function as the state variables of the oscillator mechanism (4). This model predicts that these core clock genes also should influence the rhythmic expression of ''output'' genes important in regulating physiologic and biologic processes controlled by the circadian clock (5).Previous screens for such clock-controlled output genes have yielded varying estimates of their abundance and character in different organisms. An insertional reporter screen in the photosynthetic prokaryote Synechococcus suggested that most genes in this organism are transcribed in circadian fashion (6). Using microarray analysis, Harmer et al. identified 453 genes undergoing rhythmic expression under constant conditions in the plant Arabidopsis thaliana (7), representing Ϸ6% of the expressed genome. In Drosophila, analysis of 280 expressed sequence tags from the fly head revealed 20 diurnally varying transcripts, the majority of which were extremely rare, long messages of unclear physiologic function (8). The full extent of circadian gene expression is not known in any organism. The recent availability of an oligonucleotide-based microarray containing probes for nearly all known and predicted Drosophila genes allows estimation of the number of clock-controlled genes in the fly. Here we describe results of measuring circadian gene expression in control and period mutant flies in both light-dark (LD) and freerunning conditions. While this article was in preparation, three ot...

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“…Similarly, Feb 211-, Mai 301-, or Mai 369-driven UAS-NF1 expression in subsets of neurons that innervate the ring gland (Siegmund and Korge 2001) did not restore normal growth. Among the drivers expressed in peptidergic neurons, only the relatively widely expressed GAL4-386Y driver (Taghert et al 2001) allowed partial rescue. No rescue was observed upon expressing UAS-NF1 in dopaminergic neurons using two Ddc-GAL4 drivers (Li et al 2000), in cholinergic neurons using Cha-GAL4 19B (Salvaterra and Kitamoto 2001), in amnesiac-expressing cells using the amn c651 driver (Waddell et al 2000), or in insulin-producing neu- Wing area measurements were made using NIH Image 1.62 (n = 16).…”

Section: Nf1 Functions In Larval Neurons To Regulate Growth Non-cell-mentioning

confidence: 99%

Reduced growth of Drosophila neurofibromatosis 1 mutants reflects a non-cell-autonomous requirement for GTPase-Activating Protein activity in larval neurons

Walker¹,

Tchoudakova²,

McKenney³

et al. 2006

Genes Dev.

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Neurofibromatosis type 1 (NF1) is among the most common genetic disorders of humans and is caused by loss of neurofibromin, a large and highly conserved protein whose only known function is to serve as a GTPase-Activating Protein (GAP) for Ras. However, most Drosophila NF1 mutant phenotypes, including an overall growth deficiency, are not readily modified by manipulating Ras signaling strength, but are rescued by increasing signaling through the cAMP-dependent protein kinase A pathway. This has led to suggestions that NF1 has distinct Ras-and cAMP-related functions. Here we report that the Drosophila NF1 growth defect reflects a non-cell-autonomous requirement for NF1 in larval neurons that express the R-Ras ortholog Ras2, that NF1 is a GAP for Ras1 and Ras2, and that a functional NF1-GAP catalytic domain is both necessary and sufficient for rescue. Moreover, a Drosophila p120RasGAP ortholog, when expressed in the appropriate cells, can substitute for NF1 in growth regulation. Our results show that loss of NF1 can give rise to non-cell-autonomous developmental defects, implicate aberrant Ras-mediated signaling in larval neurons as the primary cause of the NF1 growth deficiency, and argue against the notion that neurofibromin has separable Ras-and cAMP-related functions.[Keywords: Neurofibromatosis type 1; organismal growth control; non-cell autonomy; Ras signal transduction; Drosophila melanogaster]Supplemental material is available at http://www.genesdev.org. Neurofibromatosis type 1 (NF1, OMIM 162200) is a common genetic disorder, affecting two to three per 10,000 live births worldwide (Huson and Hughes 1994). NF1 patients are predisposed toward developing a variety of defects, the most characteristic of which include areas of abnormal skin pigmentation and benign tumors associated with peripheral nerves, termed neurofibromas. Less universal but more serious symptoms also include malignant peripheral nerve sheath tumors, other malignancies, and learning disabilities. Developmental abnormalities, such as specific skeletal defects, macrocephaly, and short stature, are also associated with NF1 (Huson and Hughes 1994). The >2800-amino-acid NF1 protein, termed neurofibromin, includes a segment related to the catalytic domains of Ras-specific GTPase-Activating Proteins (GAPs), and ample evidence supports the notion that the ability of neurofibromin to inactivate Ras plays a critical role in the development of NF1-associated tumors (Cichowski and Jacks 2001). The GAP-related domain (GRD) constitutes only ∼15% of neurofibromin, however, and it is less clear whether Ras signaling defects are also the immediate cause of other disease symptoms.A Drosophila melanogaster NF1 ortholog predicts a protein that is ∼60% identical to human neurofibromin over its entire length. We previously reported that Drosophila NF1-null mutants are viable, fertile, and normally patterned, but display a 15%-20% reduction in linear dimensions during all stages of post-embryonic

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Multiple Amidated Neuropeptides Are Required for Normal Circadian Locomotor Rhythms inDrosophila

Cited by 124 publications

References 37 publications

Drosophila neuropeptide F and its receptor, NPFR1, define a signaling pathway that acutely modulates alcohol sensitivity

Drosophila neuropeptide F and its receptor, NPFR1, define a signaling pathway that acutely modulates alcohol sensitivity

Influence of the period -dependent circadian clock on diurnal, circadian, and aperiodic gene expression in Drosophila melanogaster

Reduced growth of Drosophila neurofibromatosis 1 mutants reflects a non-cell-autonomous requirement for GTPase-Activating Protein activity in larval neurons

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