Publications by authors named "Michael J Pankratz"

31 Publications

Unveiling the sensory and interneuronal pathways of the neuroendocrine connectome in .

Elife 2021 06 4;10. Epub 2021 Jun 4.

Department of Molecular Brain Physiology and Behavior, LIMES Institute, University of Bonn, Bonn, Germany.

Neuroendocrine systems in animals maintain organismal homeostasis and regulate stress response. Although a great deal of work has been done on the neuropeptides and hormones that are released and act on target organs in the periphery, the synaptic inputs onto these neuroendocrine outputs in the brain are less well understood. Here, we use the transmission electron microscopy reconstruction of a whole central nervous system in the larva to elucidate the sensory pathways and the interneurons that provide synaptic input to the neurosecretory cells projecting to the endocrine organs. Predicted by network modeling, we also identify a new carbon dioxide-responsive network that acts on a specific set of neurosecretory cells and that includes those expressing corazonin (Crz) and diuretic hormone 44 (Dh44) neuropeptides. Our analysis reveals a neuronal network architecture for combinatorial action based on sensory and interneuronal pathways that converge onto distinct combinations of neuroendocrine outputs.
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http://dx.doi.org/10.7554/eLife.65745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177888PMC
June 2021

A population of neurons that produce hugin and express the diuretic hormone 44 receptor gene projects to the corpora allata in Drosophila melanogaster.

Dev Growth Differ 2021 May 17;63(4-5):249-261. Epub 2021 Jun 17.

Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan.

The corpora allata (CA) are essential endocrine organs that biosynthesize and secrete the sesquiterpenoid hormone, namely juvenile hormone (JH), to regulate a wide variety of developmental and physiological events in insects. CA are directly innervated with neurons in many insect species, implying the innervations to be important for regulating JH biosynthesis. Although this is also true for the model organism Drosophila melanogaster, neurotransmitters produced in the CA-projecting neurons are yet to be identified. In this study on D. melanogaster, we aimed to demonstrate that a subset of neurons producing the neuropeptide hugin, the invertebrate counterpart of the vertebrate neuromedin U, directly projects to the adult CA. A synaptic vesicle marker in the hugin neurons was observed at their axon termini located on the CA, which were immunolabeled with a newly-generated antibody to the JH biosynthesis enzyme JH acid O-methyltransferase. We also found the CA-projecting hugin neurons to likely express a gene encoding the specific receptor for diuretic hormone 44 (Dh44). Moreover, our data suggest that the CA-projecting hugin neurons have synaptic connections with the upstream neurons producing Dh44. Unexpectedly, the inhibition of CA-projecting hugin neurons did not significantly alter the expression levels of the JH-inducible gene Krüppel-homolog 1, which implies that the CA-projecting neurons are not involved in JH biosynthesis but rather in other known biological processes. This is the first study to identify a specific neurotransmitter of the CA-projecting neurons in D. melanogaster, and to anatomically characterize a neuronal pathway of the CA-projecting neurons and their upstream neurons.
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http://dx.doi.org/10.1111/dgd.12733DOI Listing
May 2021

Making Feeding Decisions in the Drosophila Nervous System.

Curr Biol 2020 07;30(14):R831-R840

Molecular Brain Physiology and Behavior, Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl Troll Str. 31, 53115 Bonn, Germany. Electronic address:

Feeding is one of the most fundamental activities of animals. Whether an animal will eat or not depends on sensory cues concerning nutrient availability and quality as well as on its growth, hormonal and metabolic state. These diverse signals, which originate from different regions of the body and act on different time scales, must be integrated by the nervous system to enable an appropriate feeding response. Here, we review recent studies in Drosophila melanogaster larvae that aim to elucidate the central circuits that underlie food intake, based on a serial section electron microscopic volume of an entire central nervous system. We focus on the comprehensive mapping of the synaptic connections between the sensory inputs and motor outputs of the larval feeding system. The central feeding circuit can be organized into a series of parallel pathways that connect a given set of input and output neurons. A dominant circuit motif is that of a monosynaptic sensory-motor connection upon which a series of polysynaptic paths are superimposed. The interneurons of the different parallel paths receive slightly different sets of sensory inputs, which enable flexibility in the selection of feeding motor outputs.
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http://dx.doi.org/10.1016/j.cub.2020.06.036DOI Listing
July 2020

The Corazonin-PTTH Neuronal Axis Controls Systemic Body Growth by Regulating Basal Ecdysteroid Biosynthesis in Drosophila melanogaster.

Curr Biol 2020 06 7;30(11):2156-2165.e5. Epub 2020 May 7.

Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, 305-8577 Tsukuba, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.

Steroid hormones play key roles in development, growth, and reproduction in various animal phyla [1]. The insect steroid hormone, ecdysteroid, coordinates growth and maturation, represented by molting and metamorphosis [2]. In Drosophila melanogaster, the prothoracicotropic hormone (PTTH)-producing neurons stimulate peak levels of ecdysteroid biosynthesis for maturation [3]. Additionally, recent studies on PTTH signaling indicated that basal levels of ecdysteroid negatively affect systemic growth prior to maturation [4-8]. However, it remains unclear how PTTH signaling is regulated for basal ecdysteroid biosynthesis. Here, we report that Corazonin (Crz)-producing neurons regulate basal ecdysteroid biosynthesis by affecting PTTH neurons. Crz belongs to gonadotropin-releasing hormone (GnRH) superfamily, implying an analogous role in growth and maturation [9]. Inhibition of Crz neuronal activity increased pupal size, whereas it hardly affected pupariation timing. This phenotype resulted from enhanced growth rate and a delay in ecdysteroid elevation during the mid-third instar larval (L3) stage. Interestingly, Crz receptor (CrzR) expression in PTTH neurons was higher during the mid- than the late-L3 stage. Silencing of CrzR in PTTH neurons increased pupal size, phenocopying the inhibition of Crz neuronal activity. When Crz neurons were optogenetically activated, a strong calcium response was observed in PTTH neurons during the mid-L3, but not the late-L3, stage. Furthermore, we found that octopamine neurons contact Crz neurons in the subesophageal zone (SEZ), transmitting signals for systemic growth. Together, our results suggest that the Crz-PTTH neuronal axis modulates ecdysteroid biosynthesis in response to octopamine, uncovering a regulatory neuroendocrine system in the developmental transition from growth to maturation.
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http://dx.doi.org/10.1016/j.cub.2020.03.050DOI Listing
June 2020

Convergence of monosynaptic and polysynaptic sensory paths onto common motor outputs in a feeding connectome.

Elife 2018 12 11;7. Epub 2018 Dec 11.

Department of Molecular Brain Physiology and Behavior, LIMES Institute, University of Bonn, Bonn, Germany.

We reconstructed, from a whole CNS EM volume, the synaptic map of input and output neurons that underlie food intake behavior of larvae. Input neurons originate from enteric, pharyngeal and external sensory organs and converge onto seven distinct sensory synaptic compartments within the CNS. Output neurons consist of feeding motor, serotonergic modulatory and neuroendocrine neurons. Monosynaptic connections from a set of sensory synaptic compartments cover the motor, modulatory and neuroendocrine targets in overlapping domains. Polysynaptic routes are superimposed on top of monosynaptic connections, resulting in divergent sensory paths that converge on common outputs. A completely different set of sensory compartments is connected to the mushroom body calyx. The mushroom body output neurons are connected to interneurons that directly target the feeding output neurons. Our results illustrate a circuit architecture in which monosynaptic and multisynaptic connections from sensory inputs traverse onto output neurons via a series of converging paths.
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http://dx.doi.org/10.7554/eLife.40247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289573PMC
December 2018

Serotonergic network in the subesophageal zone modulates the motor pattern for food intake in Drosophila.

J Insect Physiol 2018 04 19;106(Pt 1):36-46. Epub 2017 Jul 19.

Department of Molecular Brain Physiology, Limes Institute, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany.

The functional organization of central motor circuits underlying feeding behaviors is not well understood. We have combined electrophysiological and genetic approaches to investigate the regulatory networks upstream of the motor program underlying food intake in the Drosophila larval central nervous system. We discovered that the serotonergic network of the CNS is able to set the motor rhythm frequency of pharyngeal pumping. Pharmacological experiments verified that modulation of the feeding motor pattern is based on the release of serotonin. Classical lesion and laser based cell ablation indicated that the serotonergic neurons in the subesophageal zone represent a redundant network for motor control of larval food intake.
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http://dx.doi.org/10.1016/j.jinsphys.2017.07.007DOI Listing
April 2018

The Olmpiad: concordance of behavioural faculties of stage 1 and stage 3 larvae.

J Exp Biol 2017 07;220(Pt 13):2452-2475

Center for Molecular Neurobiology, University of Hamburg, 20251 Hamburg, Germany.

Mapping brain function to brain structure is a fundamental task for neuroscience. For such an endeavour, the larva is simple enough to be tractable, yet complex enough to be interesting. It features about 10,000 neurons and is capable of various taxes, kineses and Pavlovian conditioning. All its neurons are currently being mapped into a light-microscopical atlas, and Gal4 strains are being generated to experimentally access neurons one at a time. In addition, an electron microscopic reconstruction of its nervous system seems within reach. Notably, this electron microscope-based connectome is being drafted for a stage 1 larva - because stage 1 larvae are much smaller than stage 3 larvae. However, most behaviour analyses have been performed for stage 3 larvae because their larger size makes them easier to handle and observe. It is therefore warranted to either redo the electron microscopic reconstruction for a stage 3 larva or to survey the behavioural faculties of stage 1 larvae. We provide the latter. In a community-based approach we called the Olmpiad, we probed stage 1 larvae for free locomotion, feeding, responsiveness to substrate vibration, gentle and nociceptive touch, burrowing, olfactory preference and thermotaxis, light avoidance, gustatory choice of various tastants plus odour-taste associative learning, as well as light/dark-electric shock associative learning. Quantitatively, stage 1 larvae show lower scores in most tasks, arguably because of their smaller size and lower speed. Qualitatively, however, stage 1 larvae perform strikingly similar to stage 3 larvae in almost all cases. These results bolster confidence in mapping brain structure and behaviour across developmental stages.
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http://dx.doi.org/10.1242/jeb.156646DOI Listing
July 2017

Pathogen-induced food evasion behavior in larvae.

J Exp Biol 2017 05 2;220(Pt 10):1774-1780. Epub 2017 Mar 2.

Department of Molecular Brain Physiology, LIMES Institute, University of Bonn, Carl Troll Strasse 31, Bonn 53115, Germany

Recognizing a deadly pathogen and generating an appropriate immune reaction is essential for any organism to survive in its natural habitat. Unlike vertebrates and higher primates, invertebrates depend solely on the innate immune system to defend themselves from an attacking pathogen. In this study, we report a behavioral defense strategy observed in larvae that helps them escape and limit an otherwise lethal infection. A bacterial infection in the gut is sensed by the larval central nervous system, which generates an alteration in the larva's food preference, leading it to stop feeding and move away from the infectious food source. We have also found that this behavioral response is dependent on the internal nutritive state of the larvae. Using this novel behavioral assay as a read-out, we further identified hugin neuropeptide to be involved in the evasion response and detection of bacterial signals.
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http://dx.doi.org/10.1242/jeb.153395DOI Listing
May 2017

Synaptic transmission parallels neuromodulation in a central food-intake circuit.

Elife 2016 11 15;5. Epub 2016 Nov 15.

Department of Molecular Brain Physiology and Behavior, LIMES Institute, University of Bonn, Bonn, Germany.

NeuromedinU is a potent regulator of food intake and activity in mammals. In , neurons producing the homologous neuropeptide hugin regulate feeding and locomotion in a similar manner. Here, we use EM-based reconstruction to generate the entire connectome of hugin-producing neurons in the larval CNS. We demonstrate that hugin neurons use synaptic transmission in addition to peptidergic neuromodulation and identify acetylcholine as a key transmitter. Hugin neuropeptide and acetylcholine are both necessary for the regulatory effect on feeding. We further show that subtypes of hugin neurons connect chemosensory to endocrine system by combinations of synaptic and peptide-receptor connections. Targets include endocrine neurons producing DH44, a CRH-like peptide, and insulin-like peptides. Homologs of these peptides are likewise downstream of neuromedinU, revealing striking parallels in flies and mammals. We propose that hugin neurons are part of an ancient physiological control system that has been conserved at functional and molecular level.
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http://dx.doi.org/10.7554/eLife.16799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182061PMC
November 2016

Central relay of bitter taste to the protocerebrum by peptidergic interneurons in the Drosophila brain.

Nat Commun 2016 09 13;7:12796. Epub 2016 Sep 13.

Department of Molecular Brain Physiology and Behavior, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany.

Bitter is a taste modality associated with toxic substances evoking aversive behaviour in most animals, and the valence of different taste modalities is conserved between mammals and Drosophila. Despite knowledge gathered in the past on the peripheral perception of taste, little is known about the identity of taste interneurons in the brain. Here we show that hugin neuropeptide-containing neurons in the Drosophila larval brain are necessary for avoidance behaviour to caffeine, and when activated, result in cessation of feeding and mediates a bitter taste signal within the brain. Hugin neuropeptide-containing neurons project to the neurosecretory region of the protocerebrum and functional imaging demonstrates that these neurons are activated by bitter stimuli and by activation of bitter sensory receptor neurons. We propose that hugin neurons projecting to the protocerebrum act as gustatory interneurons relaying bitter taste information to higher brain centres in Drosophila larvae.
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http://dx.doi.org/10.1038/ncomms12796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027282PMC
September 2016

Neuroscience: Hunger Pangs in the Fly Brain.

Curr Biol 2016 08;26(15):R701-R703

Molecular Brain Physiology and Behavior, Limes Institute, University of Bonn, Bonn, Germany. Electronic address:

Which neurons in the brain become engaged when the body is deprived of food? A new study addresses this question using the vinegar fly Drosophila melanogaster, examining a group of neurons in the brain that show alterations in neural activity when flies are satiated or starved.
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http://dx.doi.org/10.1016/j.cub.2016.06.060DOI Listing
August 2016

Localization of Motor Neurons and Central Pattern Generators for Motor Patterns Underlying Feeding Behavior in Drosophila Larvae.

PLoS One 2015 7;10(8):e0135011. Epub 2015 Aug 7.

LIMES-Institute, University of Bonn, 53115, Bonn, Germany.

Motor systems can be functionally organized into effector organs (muscles and glands), the motor neurons, central pattern generators (CPG) and higher control centers of the brain. Using genetic and electrophysiological methods, we have begun to deconstruct the motor system driving Drosophila larval feeding behavior into its component parts. In this paper, we identify distinct clusters of motor neurons that execute head tilting, mouth hook movements, and pharyngeal pumping during larval feeding. This basic anatomical scaffold enabled the use of calcium-imaging to monitor the neural activity of motor neurons within the central nervous system (CNS) that drive food intake. Simultaneous nerve- and muscle-recordings demonstrate that the motor neurons innervate the cibarial dilator musculature (CDM) ipsi- and contra-laterally. By classical lesion experiments we localize a set of CPGs generating the neuronal pattern underlying feeding movements to the subesophageal zone (SEZ). Lesioning of higher brain centers decelerated all feeding-related motor patterns, whereas lesioning of ventral nerve cord (VNC) only affected the motor rhythm underlying pharyngeal pumping. These findings provide a basis for progressing upstream of the motor neurons to identify higher regulatory components of the feeding motor system.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135011PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529123PMC
May 2016

Single serotonergic neurons that modulate aggression in Drosophila.

Curr Biol 2014 Nov 30;24(22):2700-7. Epub 2014 Oct 30.

Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.

Monoamine serotonin (5HT) has been linked to aggression for many years across species. However, elaboration of the neurochemical pathways that govern aggression has proven difficult because monoaminergic neurons also regulate other behaviors. There are approximately 100 serotonergic neurons in the Drosophila nervous system, and they influence sleep, circadian rhythms, memory, and courtship. In the Drosophila model of aggression, the acute shut down of the entire serotonergic system yields flies that fight less, whereas induced activation of 5HT neurons promotes aggression. Using intersectional genetics, we restricted the population of 5HT neurons that can be reproducibly manipulated to identify those that modulate aggression. Although similar approaches were used recently to find aggression-modulating dopaminergic and Fru(M)-positive peptidergic neurons, the downstream anatomical targets of the neurons that make up aggression-controlling circuits remain poorly understood. Here, we identified a symmetrical pair of serotonergic PLP neurons that are necessary for the proper escalation of aggression. Silencing these neurons reduced aggression in male flies, and activating them increased aggression in male flies. GFP reconstitution across synaptic partners (GRASP) analyses suggest that 5HT-PLP neurons form contacts with 5HT1A receptor-expressing neurons in two distinct anatomical regions of the brain. Activation of these 5HT1A receptor-expressing neurons, in turn, caused reductions in aggression. Our studies, therefore, suggest that aggression may be held in check, at least in part, by inhibitory input from 5HT1A receptor-bearing neurons, which can be released by activation of the 5HT-PLP neurons.
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http://dx.doi.org/10.1016/j.cub.2014.09.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254562PMC
November 2014

Selection of motor programs for suppressing food intake and inducing locomotion in the Drosophila brain.

PLoS Biol 2014 Jun 24;12(6):e1001893. Epub 2014 Jun 24.

Molecular Brain Physiology and Behavior, LIMES-Institute, University of Bonn, Germany.

Central mechanisms by which specific motor programs are selected to achieve meaningful behaviors are not well understood. Using electrophysiological recordings from pharyngeal nerves upon central activation of neurotransmitter-expressing cells, we show that distinct neuronal ensembles can regulate different feeding motor programs. In behavioral and electrophysiological experiments, activation of 20 neurons in the brain expressing the neuropeptide hugin, a homolog of mammalian neuromedin U, simultaneously suppressed the motor program for food intake while inducing the motor program for locomotion. Decreasing hugin neuropeptide levels in the neurons by RNAi prevented this action. Reducing the level of hugin neuronal activity alone did not have any effect on feeding or locomotion motor programs. Furthermore, use of promoter-specific constructs that labeled subsets of hugin neurons demonstrated that initiation of locomotion can be separated from modulation of its motor pattern. These results provide insights into a neural mechanism of how opposing motor programs can be selected in order to coordinate feeding and locomotive behaviors.
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http://dx.doi.org/10.1371/journal.pbio.1001893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068981PMC
June 2014

Serotonergic pathways in the Drosophila larval enteric nervous system.

J Insect Physiol 2014 Oct 4;69:118-25. Epub 2014 Jun 4.

Department of Molecular Brain Physiology, LIMES Institute, University of Bonn, Carl Troll Str. 31, 53115 Bonn, Germany. Electronic address:

The enteric nervous system is critical for coordinating diverse feeding-related behaviors and metabolism. We have characterized a cluster of four serotonergic neurons in Drosophila larval brain: cell bodies are located in the subesophageal ganglion (SOG) whose neuronal processes project into the enteric nervous system. Electrophysiological, calcium imaging and behavioral analyses indicate a functional role of these neurons in modulating foregut motility. We suggest that the axonal projections of this serotonergic cluster may be part of a brain-gut neural pathway that is functionally analogous to the vertebrate vagus nerve.
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http://dx.doi.org/10.1016/j.jinsphys.2014.05.022DOI Listing
October 2014

Src tyrosine kinase signaling antagonizes nuclear localization of FOXO and inhibits its transcription factor activity.

Sci Rep 2014 Feb 11;4:4048. Epub 2014 Feb 11.

Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zurich, 8093 Zurich, Switzerland.

Biochemical experiments in mammalian cells have linked Src family kinase activity to the insulin signaling pathway. To explore the physiological link between Src and a central insulin pathway effector, we investigated the effect of different Src signaling levels on the Drosophila transcription factor dFOXO in vivo. Ectopic activation of Src42A in the starved larval fatbody was sufficient to drive dFOXO out of the nucleus. When Src signaling levels were lowered by means of loss-of-function mutations or pharmacological inhibition, dFOXO localization was shifted to the nucleus in growing animals, and transcription of the dFOXO target genes d4E-BP and dInR was induced. dFOXO loss-of-function mutations rescued the induction of dFOXO target gene expression and the body size reduction of Src42A mutant larvae, establishing dFOXO as a critical downstream effector of Src signaling. Furthermore, we provide evidence that the regulation of FOXO transcription factors by Src is evolutionarily conserved in mammalian cells.
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http://dx.doi.org/10.1038/srep04048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920272PMC
February 2014

The Drosophila FoxA ortholog Fork head regulates growth and gene expression downstream of Target of rapamycin.

PLoS One 2010 Dec 31;5(12):e15171. Epub 2010 Dec 31.

Institute of Molecular Systems Biology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.

Forkhead transcription factors of the FoxO subfamily regulate gene expression programs downstream of the insulin signaling network. It is less clear which proteins mediate transcriptional control exerted by Target of rapamycin (TOR) signaling, but recent studies in nematodes suggest a role for FoxA transcription factors downstream of TOR. In this study we present evidence that outlines a similar connection in Drosophila, in which the FoxA protein Fork head (FKH) regulates cellular and organismal size downstream of TOR. We find that ectopic expression and targeted knockdown of FKH in larval tissues elicits different size phenotypes depending on nutrient state and TOR signaling levels. FKH overexpression has a negative effect on growth under fed conditions, and this phenotype is not further exacerbated by inhibition of TOR via rapamycin feeding. Under conditions of starvation or low TOR signaling levels, knockdown of FKH attenuates the size reduction associated with these conditions. Subcellular localization of endogenous FKH protein is shifted from predominantly cytoplasmic on a high-protein diet to a pronounced nuclear accumulation in animals with reduced levels of TOR or fed with rapamycin. Two putative FKH target genes, CG6770 and cabut, are transcriptionally induced by rapamycin or FKH expression, and silenced by FKH knockdown. Induction of both target genes in heterozygous TOR mutant animals is suppressed by mutations in fkh. Furthermore, TOR signaling levels and FKH impact on transcription of the dFOXO target gene d4E-BP, implying a point of crosstalk with the insulin pathway. In summary, our observations show that an alteration of FKH levels has an effect on cellular and organismal size, and that FKH function is required for the growth inhibition and target gene induction caused by low TOR signaling levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015171PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3013099PMC
December 2010

Making metabolic decisions in Drosophila.

Fly (Austin) 2009 Jan-Mar;3(1):74-7. Epub 2009 Jan 8.

Molecular Physiology and Genetics Unit, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.

Physiology and behavior have historically been treated as separate subjects in the study of Drosophila. The latter is mentioned mainly in the context of neurobiology, while the former has been considered to take in studies of metabolism, cell biology and anatomy, among others. Of late, the line distinguishing physiology and behavior has become thinner, and this is exceptionally apparent in recent studies of nutrient signaling and of the regulation of feeding. This review represents a brief examination of the nexus between these intersecting fields of research in Drosophila. Other recently published reviews serve as complements to this one.
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http://dx.doi.org/10.4161/fly.3.1.7795DOI Listing
September 2009

Comparative neuroanatomy and genomics of hugin and pheromone biosynthesis activating neuropeptide (PBAN).

Fly (Austin) 2007 Jul-Aug;1(4):228-31. Epub 2007 Jul 16.

Institut für Genetik, Forschungszentrum Karlsruhe, Karlsruhe, Germany.

The Drosophila hugin gene encodes a prepropeptide that can potentially generate several neuropeptides.(1) The gene is expressed in 20 cells of the subesophageal ganglion (SOG) that are involved in modulating feeding behavior.(2) One of the hugin neuropeptides shares homology with mammalian neuromedin U8 (NmU8), which has been shown to regulate feeding behavior in rodents.(3,4) Recent clonal analysis indicated that each hugin expressing neuron projects to one of four main targets: the protocerebrum, the ventral nerve cord, the pharynx and the corpora cardiaca.(5) In addition all hugin neurons send short neurites to a novel region ventro-lateral to the foramen, which we suggested could be the tritocerebrum. In this short article, we discuss two specific issues brought up by these analyses. One concerns the polarity of hugin neurons. The other is an evolutionary perspective on the processing of hugin neuropeptides in light of new data from mass spectrometric and genomic analyses.
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http://dx.doi.org/10.4161/fly.4749DOI Listing
November 2008

Opposing effects of dietary protein and sugar regulate a transcriptional target of Drosophila insulin-like peptide signaling.

Cell Metab 2008 Apr;7(4):321-32

Institute of Genetics, Forschungszentrum Karlsruhe, 76021 Karlsruhe, Germany.

Specific neurosecretory cells of the Drosophila brain express insulin-like peptides (dilps), which regulate growth, glucose homeostasis, and aging. Through microarray analysis of flies in which the insulin-producing cells (IPCs) were ablated, we identified a target gene, target of brain insulin (tobi), that encodes an evolutionarily conserved alpha-glucosidase. Flies with lowered tobi levels are viable, whereas tobi overexpression causes severe growth defects and a decrease in body glycogen. Interestingly, tobi expression is increased by dietary protein and decreased by dietary sugar. This pattern is reminiscent of mammalian glucagon secretion, which is increased by protein intake and decreased by sugar intake, suggesting that tobi is regulated by a glucagon analog. tobi expression is also eliminated upon ablation of neuroendocrine cells that produce adipokinetic hormone (AKH), an analog of glucagon. tobi is thus a target of the insulin- and glucagon-like signaling system that responds oppositely to dietary protein and sugar.
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http://dx.doi.org/10.1016/j.cmet.2008.02.012DOI Listing
April 2008

The TATA-binding protein regulates maternal mRNA degradation and differential zygotic transcription in zebrafish.

EMBO J 2007 Sep 16;26(17):3945-56. Epub 2007 Aug 16.

Institute of Toxicology and Genetics, Forschungszentrum Karlsruhe, Eggenstein-Leopoldshafen, Germany.

Early steps of embryo development are directed by maternal gene products and trace levels of zygotic gene activity in vertebrates. A major activation of zygotic transcription occurs together with degradation of maternal mRNAs during the midblastula transition in several vertebrate systems. How these processes are regulated in preparation for the onset of differentiation in the vertebrate embryo is mostly unknown. Here, we studied the function of TATA-binding protein (TBP) by knock down and DNA microarray analysis of gene expression in early embryo development. We show that a subset of polymerase II-transcribed genes with ontogenic stage-dependent regulation requires TBP for their zygotic activation. TBP is also required for limiting the activation of genes during development. We reveal that TBP plays an important role in the degradation of a specific subset of maternal mRNAs during late blastulation/early gastrulation, which involves targets of the miR-430 pathway. Hence, TBP acts as a specific regulator of the key processes underlying the transition from maternal to zygotic regulation of embryogenesis. These results implicate core promoter recognition as an additional level of differential gene regulation during development.
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http://dx.doi.org/10.1038/sj.emboj.7601821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950726PMC
September 2007

Enzyme-free interrogation of RNA sites via primers and oligonucleotides 3'-linked to gold surfaces.

Org Lett 2007 May 5;9(11):2187-90. Epub 2007 May 5.

Institute of Organic Chemistry, University of Karlsruhe (TH), 76131 Karlsruhe, Germany.

The synthesis of a phosphoramidite is described that was used for the preparation of oligonucleotides with a 3'-terminal thiol, linked to the DNA via a SAM-forming undecyl chain and a nonadsorptive tetraethylene glycol unit. A gold surface featuring oligonucleotide probes allowed for label-free in situ mass spectrometric determination of a nucleotide in subpicomole quantities of an RNA transcript.
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http://dx.doi.org/10.1021/ol070724gDOI Listing
May 2007

Genetic dissection of neural circuit anatomy underlying feeding behavior in Drosophila: distinct classes of hugin-expressing neurons.

J Comp Neurol 2007 Jun;502(5):848-56

Institut für Genetik, Forschungszentrum Karlsruhe, 76021 Karlsruhe, Germany.

The hugin gene of Drosophila encodes a neuropeptide with homology to mammalian neuromedin U. The hugin-expressing neurons are localized exclusively to the subesophageal ganglion of the central nervous system and modulate feeding behavior in response to nutrient signals. These neurons send neurites to the protocerebrum, the ventral nerve cord, the ring gland, and the pharynx and may interact with the gustatory sense organs. In this study, we have investigated the morphology of the hugin neurons at a single-cell level by using clonal analysis. We show that single cells project to only one of the four major targets. In addition, the neurites of the different hugin cells overlap in a specific brain region lateral to the foramen of the esophagus, which could be a new site of neuropeptide release for feeding regulation. Our study reveals novel complexity in the morphology of individual hugin neurons, which has functional implication for how they coordinate feeding behavior and growth.
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http://dx.doi.org/10.1002/cne.21342DOI Listing
June 2007

Amino acids, taste circuits, and feeding behavior in Drosophila: towards understanding the psychology of feeding in flies and man.

J Endocrinol 2007 Mar;192(3):467-72

Institute for Genetics, Forschungszentrum Karlsruhe, Karlsruhe, Germany.

Feeding can be regulated by a variety of external sensory stimuli such as olfaction and gustation, as well as by systemic internal signals of feeding status and metabolic needs. Faced with a major health epidemic in eating-related conditions, such as obesity and diabetes, there is an ever increasing need to dissect and understand the complex regulatory network underlying the multiple aspects of feeding behavior. In this minireview, we highlight the use of Drosophila in studying the neural circuits that control the feeding behavior in response to external and internal signals. In particular, we outline the work on the neuroanatomical and functional characterization of the newly identified hugin neuronal circuit. We focus on the pivotal role of the central nervous system in integrating external and internal feeding-relevant information, thus enabling the organism to make one of the most basic decisions - to eat or not to eat.
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http://dx.doi.org/10.1677/JOE-06-0066DOI Listing
March 2007

Purine and folate metabolism as a potential target of sex-specific nutrient allocation in Drosophila and its implication for lifespan-reproduction tradeoff.

Physiol Genomics 2006 May 28;25(3):393-404. Epub 2006 Mar 28.

Institut für Genetik, Forschungszentrum Karlsruhe, Karlsruhe, Germany.

The reallocation of metabolic resources is important for survival during periods of limited nutrient intake. This has an influence on diverse physiological processes, including reproduction, repair, and aging. One important aspect of resource allocation is the difference between males and females in response to nutrient stress. We identified several groups of genes that are regulated in a sex-biased manner under complete or protein starvation. These range from expected differences in genes involved in reproductive physiology to those involved in amino acid utilization, sensory perception, immune response, and growth control. A striking difference was observed in purine and the tightly interconnected folate metabolism upon protein starvation. From these results, we conclude that the purine and folate metabolic pathway is a major point of transcriptional regulation during resource allocation and may have relevance for understanding the physiological basis for the observed tradeoff between reproduction and longevity.
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http://dx.doi.org/10.1152/physiolgenomics.00009.2006DOI Listing
May 2006

Candidate gustatory interneurons modulating feeding behavior in the Drosophila brain.

PLoS Biol 2005 Sep 30;3(9):e305. Epub 2005 Aug 30.

Institut für Genetik, Forschungszentrum Karlsruhe, Karlsruhe, Germany.

Feeding is a fundamental activity of all animals that can be regulated by internal energy status or external sensory signals. We have characterized a zinc finger transcription factor, klumpfuss (klu), which is required for food intake in Drosophila larvae. Microarray analysis indicates that expression of the neuropeptide gene hugin (hug) in the brain is altered in klu mutants and that hug itself is regulated by food signals. Neuroanatomical analysis demonstrates that hug-expressing neurons project axons to the pharyngeal muscles, to the central neuroendocrine organ, and to the higher brain centers, whereas hug dendrites are innervated by external gustatory receptor-expressing neurons, as well as by internal pharyngeal chemosensory organs. The use of tetanus toxin to block synaptic transmission of hug neurons results in alteration of food intake initiation, which is dependent on previous nutrient condition. Our results provide evidence that hug neurons function within a neural circuit that modulates taste-mediated feeding behavior.
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http://dx.doi.org/10.1371/journal.pbio.0030305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1193519PMC
September 2005

Linking nutrition to genomics.

Biol Chem 2004 Jul;385(7):593-6

Institut für Genetik, Forschungszentrum Karlsruhe, Postfach 3640, D-76021 Karlsruhe, Germany.

The new scientific field of nutrigenomics utilizes genomic tools, like microarrays, to analyze metabolic adaptations induced by variations in nutritional status. Here we describe how transcriptional regulation patterns caused by nutritional changes can be identified using gene expression profiling. This includes technical remarks on microarray analysis and data processing, as well as giving biological meaning to statistically solid data. We highlight our recent findings of transcriptional regulation of genes representing specific signaling and metabolic pathways in mouse liver under starvation. The results show strong correlations to previously identified responses to caloric restriction, which can be linked to lifespan extension.
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http://dx.doi.org/10.1515/BC.2004.073DOI Listing
July 2004

Starvation response in mouse liver shows strong correlation with life-span-prolonging processes.

Physiol Genomics 2004 Apr 13;17(2):230-44. Epub 2004 Apr 13.

Institut fuer Genetik, Forschungszentrum Karlsruhe, 76021 Karlsruhe, , Germany.

We have monitored global changes in gene expression in mouse liver in response to fasting and sugar-fed conditions using high-density microarrays. From approximately 20,000 different genes, the significantly regulated ones were grouped into specific signaling and metabolic pathways. Striking changes in lipid signaling cascade, insulin and dehydroepiandrosterone (DHEA) hormonal pathways, urea cycle and S-adenosylmethionine-based methyl transfer systems, and cell apoptosis regulators were observed. Since these pathways have been implicated to play a role in the aging process, and since we observe significant overlap of genes regulated upon starvation with those regulated upon caloric restriction, our analysis suggests that starvation may elicit a stress response that is also elicited during caloric restriction. Therefore, many of the signaling and metabolic components regulated during fasting may be the same as those which mediate caloric restriction-dependent life-span extension.
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http://dx.doi.org/10.1152/physiolgenomics.00203.2003DOI Listing
April 2004

Protein interaction maps on the fly.

Nat Biotechnol 2004 Jan;22(1):43-4

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http://dx.doi.org/10.1038/nbt0104-43DOI Listing
January 2004
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