Neurofibromin regulates metabolic rate via neuronal mechanisms in <i>Drosophila</i>

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Abstract

Neurofibromatosis type 1 is a chronic multisystemic genetic disorder that results from loss of function in the neurofibromin protein. Neurofibromin may regulate metabolism, though the underlying mechanisms remain largely unknown. Here we show that neurofibromin regulates metabolic homeostasis in Drosophila via a discrete neuronal circuit. Loss of neurofibromin increases metabolic rate via a Ras GAP-related domain-dependent mechanism, increases feeding homeostatically, and alters lipid stores and turnover kinetics. The increase in metabolic rate is independent of locomotor activity, and maps to a sparse subset of neurons. Stimulating these neurons increases metabolic rate, linking their dynamic activity state to metabolism over short time scales. Our results indicate that neurofibromin regulates metabolic rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may represent a pathophysiological mechanism in neurofibromatosis type 1, and provide a platform for investigating the cellular role of neurofibromin in metabolic homeostasis.

Abstract

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in neurofibromin and associated with disruptions in physiology and behavior. Here the authors show that neurofibromin regulates metabolic homeostasis via a discrete brain circuit in a Drosophila model of NF1.

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Most cited references 58

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A GAL4-driver line resource for Drosophila neurobiology.

Arnim Jenett, Gerald M Rubin, Teri-T B Ngo … (2012)

We established a collection of 7,000 transgenic lines of Drosophila melanogaster. Expression of GAL4 in each line is controlled by a different, defined fragment of genomic DNA that serves as a transcriptional enhancer. We used confocal microscopy of dissected nervous systems to determine the expression patterns driven by each fragment in the adult brain and ventral nerve cord. We present image data on 6,650 lines. Using both manual and machine-assisted annotation, we describe the expression patterns in the most useful lines. We illustrate the utility of these data for identifying novel neuronal cell types, revealing brain asymmetry, and describing the nature and extent of neuronal shape stereotypy. The GAL4 lines allow expression of exogenous genes in distinct, small subsets of the adult nervous system. The set of DNA fragments, each driving a documented expression pattern, will facilitate the generation of additional constructs for manipulating neuronal function. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

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A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila.

Georg Dietzl, Doris Chen, Frank Schnorrer … (2007)

Forward genetic screens in model organisms have provided important insights into numerous aspects of development, physiology and pathology. With the availability of complete genome sequences and the introduction of RNA-mediated gene interference (RNAi), systematic reverse genetic screens are now also possible. Until now, such genome-wide RNAi screens have mostly been restricted to cultured cells and ubiquitous gene inactivation in Caenorhabditis elegans. This powerful approach has not yet been applied in a tissue-specific manner. Here we report the generation and validation of a genome-wide library of Drosophila melanogaster RNAi transgenes, enabling the conditional inactivation of gene function in specific tissues of the intact organism. Our RNAi transgenes consist of short gene fragments cloned as inverted repeats and expressed using the binary GAL4/UAS system. We generated 22,270 transgenic lines, covering 88% of the predicted protein-coding genes in the Drosophila genome. Molecular and phenotypic assays indicate that the majority of these transgenes are functional. Our transgenic RNAi library thus opens up the prospect of systematically analysing gene functions in any tissue and at any stage of the Drosophila lifespan.

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Conditional modification of behavior in Drosophila by targeted expression of a temperature-sensitive shibire allele in defined neurons.

T Kitamoto (2001)

Behavior is a manifestation of temporally and spatially defined neuronal activities. To understand how behavior is controlled by the nervous system, it is important to identify the neuronal substrates responsible for these activities, and to elucidate how they are integrated into a functional circuit. I introduce a novel and general method to conditionally perturb anatomically defined neurons in intact Drosophila. In this method, a temperature-sensitive allele of shibire (shi(ts1)) is overexpressed in neuronal subsets using the GAL4/UAS system. Because the shi gene product is essential for synaptic vesicle recycling, and shi(ts1) is semidominant, a simple temperature shift should lead to fast and reversible effects on synaptic transmission of shi(ts1) expressing neurons. When shi(ts1) expression was directed to cholinergic neurons, adult flies showed a dramatic response to the restrictive temperature, becoming motionless within 2 min at 30 degrees C. This temperature-induced paralysis was reversible. After being shifted back to the permissive temperature, they readily regained their activity and started to walk in 1 min. When shi(ts1) was expressed in photoreceptor cells, adults and larvae exhibited temperature-dependent blindness. These observations show that the GAL4/UAS system can be used to express shi(ts1) in a specific subset of neurons to cause temperature-dependent changes in behavior. Because this method allows perturbation of the neuronal activities rapidly and reversibly in a spatially and temporally restricted manner, it will be useful to study the functional significance of particular neuronal subsets in the behavior of intact animals. Copyright 2001 John Wiley & Sons, Inc.

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Author and article information

Contributors

Seth M. Tomchik:

ORCID: http://orcid.org/0000-0001-5686-0833

stomchik@scripps.edu

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 13 July 2021

Publication date PMC-release: 13 July 2021

Publication date Collection: 2021

Volume: 12

Electronic Location Identifier: 4285

Affiliations

[1 ]GRID grid.214007.0, ISNI 0000000122199231, Department of Neuroscience, , The Scripps Research Institute, Scripps Florida, ; Jupiter, FL USA

[2 ]GRID grid.255951.f, ISNI 0000 0004 0635 0263, Department of Biological Sciences, , Florida Atlantic University, ; Jupiter, FL USA

[3 ]GRID grid.260293.c, ISNI 0000 0001 2162 4400, Program in Neuroscience and Behavior, , Mount Holyoke College, ; South Hadley, MA USA

[4 ]GRID grid.38142.3c, ISNI 000000041936754X, Center for Genomic Medicine, , Massachusetts General Hospital, Harvard Medical School, ; Boston, MA USA

[5 ]GRID grid.66859.34, Cancer Program, , Broad Institute of MIT and Harvard, ; Cambridge, MA USA

[6 ]GRID grid.8217.c, ISNI 0000 0004 1936 9705, Present Address: Department of Physiology, Trinity College Institute of Neuroscience, , Trinity College Dublin, ; Dublin, Ireland

Author information

Valentina Botero http://orcid.org/0000-0002-9744-3929

Elizabeth B. Brown http://orcid.org/0000-0003-0825-8199

Tamara Boto http://orcid.org/0000-0002-9974-3714

Scarlet J. Park http://orcid.org/0000-0002-1545-6284

Kenneth J. Colodner http://orcid.org/0000-0003-1830-3483

James A. Walker http://orcid.org/0000-0001-5585-698X

William W. Ja http://orcid.org/0000-0002-4003-7356

Seth M. Tomchik http://orcid.org/0000-0001-5686-0833

Article

Publisher ID: 24505

DOI: 10.1038/s41467-021-24505-x

PMC ID: 8277851

PubMed ID: 34257279

SO-VID: babb2505-556f-4266-b873-b84f2057770a

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 15 August 2019

Date accepted : 16 June 2021

Funding

Funded by: FundRef https://doi.org/10.13039/100000065, U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS);

Award ID: R01 NS114403

Award ID: R01 NS097237

Award Recipient : Seth M. Tomchik

Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)

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Keywords: neuroscience,diseases of the nervous system,neural circuits,fat metabolism,feeding behaviour

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ScienceOpen disciplines: Uncategorized

Keywords: neuroscience, diseases of the nervous system, neural circuits, fat metabolism, feeding behaviour

Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

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Neuronal Signaling

Most cited references 58

A GAL4-driver line resource for Drosophila neurobiology.

A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila.

Conditional modification of behavior in Drosophila by targeted expression of a temperature-sensitive shibire allele in defined neurons.

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