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Regulation of insulin signaling and its developmental and functional roles on peptidergic neurons in the Drosophila central nervous system
Stockholm University, Faculty of Science, Department of Zoology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In Drosophila, eight insulin-like peptides (DILP1-8) are produced and secreted in different locations. They regulate many aspects of development and physiology, such as organism growth, metabolic homeostasis, reproduction, stress resistance and life span. DILP2, 3 and 5 are mainly produced by a cluster of median neurosecretory cells in the brain known as insulin producing cells (IPCs). Here we showed that IPCs are under tight regulation of two G-protein coupled receptors (GPCRs), serotonin receptor 5-HT1A and octopamine receptor OAMB. Genetic manipulations of these two receptors in IPCs affected transcription levels of DILPs, hence altered feeding, carbohydrate levels, and resistance to stress (Paper I and II). Moreover, we showed that the insulin receptor (dInR) is strongly expressed in leucokininergic neurons (LK neurons), and selectively regulates growth of around 300 neuropeptidergic neurons expressing the bHLH transcription factor DIMMED. Overexpression of dInR in DIMM-positive neurons led to substantial neuronal growth, including cell body size, golgi apparatus and nuclear size, while knockdown of dInR had the opposite effect (Paper III). Manipulations of components in the insulin signaling pathway in LK neurons resulted in the similar cell size phenotypes. Furthermore, dInR regulated size scaling of DIMM-postive neurons is nutrient-dependent and partially requires the presence of DIMM (Paper III). Finally, we investigated the roles of DILPs (2, 3, 5 and 7) and LK neurons in regulation of feeding and diuresis at the adult stage (Paper IV).  In summary, we have identified two more regulators for IPC activity and demonstrated developmental roles of  DILPs and dInR in regulating neuronal size. Moreover, DILPs regulate water homeostasis together with a diuretic hormone leucokinin and as a consequence affects feeding behavior.

Place, publisher, year, edition, pages
Stockholm: Department of Zoology, Stockholm University , 2013. , 40 p.
Keyword [en]
Insulin, serotonin, octopamine, insulin receptor, Dimm, neuropeptide
National Category
Zoology
Research subject
Functional Zoomorphology
Identifiers
URN: urn:nbn:se:su:diva-96050ISBN: 978-91-7447-817-4 (print)OAI: oai:DiVA.org:su-96050DiVA: diva2:662924
Public defence
2013-12-13, William-Olssonsalen, Geovetenskapens hus, Svante Arrheniusvägen 14, Stockholm, 13:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: In press. Paper 4: Manuscript.

Available from: 2013-11-21 Created: 2013-11-08 Last updated: 2016-01-04Bibliographically approved
List of papers
1. Insulin-producing cells in the brain of adult Drosophila are regulated by the serotonin 5-HT(1A) receptor.
Open this publication in new window or tab >>Insulin-producing cells in the brain of adult Drosophila are regulated by the serotonin 5-HT(1A) receptor.
2011 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 69, no 3, 471-484 p.Article in journal (Refereed) Published
Abstract [en]

Insulin signaling regulates lifespan, reproduction, metabolic homeostasis, and resistance to stress in the adult organism. In Drosophila, there are seven insulin-like peptides (DILP1-7). Three of these (DILP2, 3 and 5) are produced in median neurosecretory cells of the brain, designated IPCs. Previous work has suggested that production or release of DILPs in IPCs can be regulated by a factor secreted from the fat body as well as by neuronal GABA or short neuropeptide F. There is also evidence that serotonergic neurons may regulate IPCs. Here, we investigated mechanisms by which serotonin may regulate the IPCs. We show that the IPCs in adult flies express the 5-HT(1A), but not the 5-HT(1B) or 5-HT(7) receptors, and that processes of serotonergic neurons impinge on the IPC branches. Knockdown of 5-HT(1A) in IPCs by targeted RNA interference (RNAi) leads to increased sensitivity to heat, prolonged recovery after cold knockdown and decreased resistance to starvation. Lipid metabolism is also affected, but no effect on growth was seen. Furthermore, we show that DILP2-immunolevels in IPCs increase after 5-HT(1A) knockdown; this is accentuated by starvation. Heterozygous 5-HT(1A) mutant flies display the same phenotype in all assays, as seen after targeted 5-HT(1A) RNAi, and flies fed the 5-HT(1A) antagonist WAY100635 display reduced lifespan at starvation. Our findings suggest that serotonin acts on brain IPCs via the 5-HT(1A) receptor, thereby affecting their activity and probably insulin signaling. Thus, we have identified a second inhibitory pathway regulating IPC activity in the Drosophila brain.

Keyword
5-hydroxytryptamine, Insulin signaling, G-protein-coupled receptor, Lifespan, Stress resistance
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-65955 (URN)10.1007/s00018-011-0789-0 (DOI)000299091500014 ()21818550 (PubMedID)
Funder
Swedish Research Council
Available from: 2011-12-16 Created: 2011-12-16 Last updated: 2017-12-08Bibliographically approved
2. Insulin producing cells are differentially regulated by serotonin and octopamine receptors
Open this publication in new window or tab >>Insulin producing cells are differentially regulated by serotonin and octopamine receptors
(English)Manuscript (preprint) (Other academic)
National Category
Cell Biology
Identifiers
urn:nbn:se:su:diva-96071 (URN)
Available from: 2013-11-11 Created: 2013-11-11 Last updated: 2014-10-28Bibliographically approved
3. Insulin/IGF-Regulated Size Scaling of Neuroendocrine Cells Expressing the bHLH Transcription Factor Dimmed in Drosophila
Open this publication in new window or tab >>Insulin/IGF-Regulated Size Scaling of Neuroendocrine Cells Expressing the bHLH Transcription Factor Dimmed in Drosophila
2013 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 12, e1004052Article in journal (Refereed) Published
Abstract [en]

Neurons and other cells display a large variation in size in an organism. Thus, a fundamental question is how growth of individual cells and their organelles is regulated. Is size scaling of individual neurons regulated post-mitotically, independent of growth of the entire CNS? Although the role of insulin/IGF-signaling (IIS) in growth of tissues and whole organisms is well established, it is not known whether it regulates the size of individual neurons. We therefore studied the role of IIS in the size scaling of neurons in the Drosophila CNS. By targeted genetic manipulations of insulin receptor (dInR) expression in a variety of neuron types we demonstrate that the cell size is affected only in neuroendocrine cells specified by the bHLH transcription factor DIMMED (DIMM). Several populations of DIMM-positive neurons tested displayed enlarged cell bodies after overexpression of the dInR, as well as PI3 kinase and Akt1 (protein kinase B), whereas DIMM-negative neurons did not respond to dInR manipulations. Knockdown of these components produce the opposite phenotype. Increased growth can also be induced by targeted overexpression of nutrient-dependent TOR (target of rapamycin) signaling components, such as Rheb (small GTPase), TOR and S6K (S6 kinase). After Dimm-knockdown in neuroendocrine cells manipulations of dInR expression have significantly less effects on cell size. We also show that dInR expression in neuroendocrine cells can be altered by up or down-regulation of Dimm. This novel dInR-regulated size scaling is seen during postembryonic development, continues in the aging adult and is diet dependent. The increase in cell size includes cell body, axon terminations, nucleus and Golgi apparatus. We suggest that the dInR-mediated scaling of neuroendocrine cells is part of a plasticity that adapts the secretory capacity to changing physiological conditions and nutrient-dependent organismal growth.

National Category
Genetics
Research subject
Functional Zoomorphology
Identifiers
urn:nbn:se:su:diva-101253 (URN)10.1371/journal.pgen.1004052 (DOI)000330533300070 ()
Funder
Swedish Research Council, 621-2010-5742
Note

AuthorCount:3;

Available from: 2014-03-03 Created: 2014-03-03 Last updated: 2017-12-05Bibliographically approved
4. Roles of insulin-like peptides and leucokinin in feeding and water homeostasis in Drosophila
Open this publication in new window or tab >>Roles of insulin-like peptides and leucokinin in feeding and water homeostasis in Drosophila
(English)Manuscript (preprint) (Other academic)
National Category
Cell Biology
Identifiers
urn:nbn:se:su:diva-96073 (URN)
Available from: 2013-11-11 Created: 2013-11-11 Last updated: 2014-10-28Bibliographically approved

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