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  • 1.
    Liu, Yiting
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Morphological and functional effects of insulin signaling and the bHLH transcription factor Dimmed on different neuron types in Drosophila2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In Drosophila, the insulin signaling pathway is at the interface between dietary conditions and control of growth and development, reproduction, stress responses and life span. Eight insulin like peptides (Dilp1-8), an insulin tyrosine kinase receptor (dInR) and its downstream components, as well as a relaxin-like receptor type (Lgr3) form the core of this signaling. Here we showed that the dInR mediates post-mitotic cell growth specifically in about 300 peptidergic neurons expressing the basic helix loop helix (bHLH) transcription factor Dimmed (Paper I).  Overexpression of dInR in Dimm positive neurons leads to increased size of cell body, Golgi apparatus and nucleus, whereas dInR knockdown causes an opposite effect. Manipulation of downstream components of insulin signaling induces similar changes in Dimm positive neurons. This mechanism is nutrient dependent. In Paper II, we further investigate the relation between Dimmed and dInR for regulation of cell growth. Coexpressing Dimm and dInR in a range of Dimm negative neurons results in increased cell size in both larval and adult stages. We provide further evidence that dInR regulates cell growth in a Dimm dependent manner and that DILP6 from glia cells is involved in this regulation. In addition, we find that Dimm alone is capable of triggering cell growth in certain neuron types at different developmental stages. Furthermore, ectopic Dimm alone can block apoptosis.  Dimm is a known master regulator of peptidergic cell fate. In paper III we find that ectopic expression of Dimm in Dimm negative motor neurons results in transformation the neurons towards a neuroendocrine phenotype. They acquire enlarged axon terminations and boutons, lose both pre- and postsynaptic markers, and display diminished levels of wingless and its receptor dFrizzled. Furthermore they show increased expression of several Dimm targets. Finally, combined ectopic Dimm and dInR expression gives rise to stronger phenotypes. In paper IV we studied another DILP possibly involved in growth regulation, the under-investigated DILP1. We generated Dilp1-Gal4 lines and anti DILP1 antibodies and found that DILP1 is transiently expressed in brain insulin producing cells (IPCs) from pupal stages to newly hatched adult flies. Diapausing virgin female flies display a high expression level of dilp1/DILP1 over at least 9 weeks of adult life. DILP1 expression is also correlated with the persistence of larval/pupal fat body and its expression is regulated by other DILPs and short neuropeptide F (sNPF). Flies mutant in dilp1 display increased food intake, but decreased stress resistance and life span. We found no obvious role of DILP1 in growth regulation.

  • 2.
    Liu, Yiting
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Liao, Sifang
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Veenstra, Jan A.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Drosophila insulin-like peptide 1 (DILP1) is transiently expressed during non-feeding stages and reproductive dormancy2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 26620Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The insulin/insulin-like growth factor signaling pathway is evolutionarily conserved in animals, and is part of nutrient-sensing mechanisms that control growth, metabolism, reproduction, stress responses, and lifespan. In Drosophila, eight insulin-like peptides (DILP1-8) are known, six of which have been investigated in some detail, whereas expression and functions of DILP1 and DILP4 remain enigmatic. Here we demonstrate that dilp1/DILP1 is transiently expressed in brain insulin producing cells (IPCs) from early pupa until a few days of adult life. However, in adult female flies where diapause is triggered by low temperature and short days, within a time window 0-10h post-eclosion, the dilp1/DILP1 expression remains high for at least 9 weeks. The dilp1 mRNA level is increased in dilp2, 3, 5 and dilp6 mutant flies, indicating feedback regulation. Furthermore, the DILP1 expression in IPCs is regulated by short neuropeptide F, juvenile hormone and presence of larval adipocytes. Male dilp1 mutant flies display increased lifespan and reduced starvation resistance, whereas in female dilp1 mutants oviposition is reduced. Thus, DILP1 is expressed in non-feeding stages and in diapausing flies, is under feedback regulation and appears to play sex-specific functional roles.

  • 3.
    Liu, Yiting
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Luo, Jiangnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen. National Institutes of Health, Bethesda, MD, USA.
    Carlsson, Mikael A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Serotonin and insulin-like peptides modulate leucokinin-producing neurons that affect feeding and water homeostasis in Drosophila2015Inngår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 523, nr 12, s. 1840-1863Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Metabolic homeostasis and water balance is maintained by tight hormonal and neuronal regulation. In Drosophila, insulin-like peptides (DILPs) are key regulators of metabolism, and the neuropeptide leucokinin (LK) is a diuretic hormone that also modulates feeding. However, it is not known whether LK and DILPs act together to regulate feeding and water homeostasis. Because LK neurons express the insulin receptor (dInR), we tested functional links between DILP and LK signaling in feeding and water balance. Thus, we performed constitutive and conditional manipulations of activity in LK neurons and insulin-producing cells (IPCs) in adult flies and monitored food intake, responses to desiccation, and peptide expression levels. We also measured in vivo changes in LK and DILP levels in neurons in response to desiccation and drinking. Our data show that activated LK cells stimulate diuresis in vivo, and that LK and IPC signaling affect food intake in opposite directions. Overexpression of the dInR in LK neurons decreases the LK peptide levels, but only caused a subtle decrease in feeding, and had no effect on water balance. Next we demonstrated that LK neurons express the serotonin receptor 5-HT1B. Knockdown of this receptor in LK neurons diminished LK expression, increased desiccation resistance, and diminished food intake. Live calcium imaging indicates that serotonin inhibits spontaneous activity in abdominal LK neurons. Our results suggest that serotonin via 5-HT1B diminishes activity in the LK neurons and thereby modulates functions regulated by LK peptide, but the action of the dInR in these neurons remains less clear.

  • 4.
    Liu, Yiting
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Luo, Jiangnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Multiple effects of the transcription factor Dimmed and the insulin receptor on growth and differentiation vary among neuron types and developmental stages in DrosophilaManuskript (preprint) (Annet vitenskapelig)
  • 5.
    Liu, Yiting
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Luo, Jiangnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    The Drosophila Transcription Factor Dimmed Affects Neuronal Growth and Differentiation in Multiple Ways Depending on Neuron Type and Developmental Stage2016Inngår i: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 9, artikkel-id 97Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Growth of postmitotic neurons occurs during different stages of development, including metamorphosis, and may also be part of neuronal plasticity and regeneration. Recently we showed that growth of post-mitotic neuroendocrine cells expressing the basic helix loop helix (bHLH) transcription factor Dimmed (Dimm) in Drosophila could be regulated by insulin/IGF signaling and the insulin receptor (dlnR). Dimm is also known to confer a secretory phenotype to neuroendocrine cells and can be part of a combinatorial code specifying terminal differentiation in peptidergic neurons. To further understand the mechanisms of Down function we ectopically expressed Dimm or Dimm together with dlnR in a wide range of Dimm positive and Dimm negative peptidergic neurons, sensory neurons, interneurons, motor neurons, and gut endocrine cells. We provide further evidence that dlnR mediated cell growth occurs in a Dimm dependent manner and that one source of insulin-like peptide (DILP) for dlnR mediated cell growth in the OHS is DILP6 from glial cells. Expressing both Dimm and dlnR in Dimm negative neurons induced growth of cell bodies, whereas dlnR alone did not. We also found that Dimm alone can regulate cell growth depending on specific cell type. This may be explained by the finding that the dlnR is a direct target of Dimm. Conditional gene targeting experiments showed that Dimm alone could affect cell growth in certain neuron types during metamorphosis or in the adult stage. Another important finding was that ectopic Dimm inhibits apoptosis of several types of neurons normally destined for programmed cell death (PCD). Taken together our results suggest that Dimm plays multiple transcriptional roles at different developmental stages in a cell type-specific manner. In some cell types ectopic Dimm may act together with resident combinatorial code transcription factors and affect terminal differentiation, as well as act in transcriptional networks that participate in long term maintenance of neurons which might lead to blocked apoptosis.

  • 6.
    Luo, Jiangnan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Liu, Yiting
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Insulin/IGF-Regulated Size Scaling of Neuroendocrine Cells Expressing the bHLH Transcription Factor Dimmed in Drosophila2013Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, nr 12, artikkel-id e1004052Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 7.
    Luo, Jiangnan
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Liu, Yiting
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Transcriptional Reorganization of Drosophila Motor Neurons and Their Muscular Junctions toward a Neuroendocrine Phenotype by the bHLH Protein Dimmed2017Inngår i: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, artikkel-id 260Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuroendocrine cells store and secrete bulk amounts of neuropeptides, and display morphological and molecular characteristics distinct from neurons signaling with classical neurotransmitters. In Drosophila the transcription factor Dimmed (Dimm), is a prime organizer of neuroendocrine capacity in a majority of the peptidergic neurons. These neurons display large cell bodies and extensive axon terminations that commonly do not form regular synapses. We ask which molecular compartments of a neuron are affected by Dimm to generate these morphological features. Thus, we ectopically expressed Dimm in glutamatergic, Dimm-negative, motor neurons and analyzed their characteristics in the central nervous system and the neuromuscular junction. Ectopic Dimm results in motor neurons with enlarged cell bodies, diminished dendrites, larger axon terminations and boutons, as well as reduced expression of synaptic proteins both pre and post-synaptically. Furthermore, the neurons display diminished vesicular glutamate transporter, and signaling components known to sustain interactions between the developing axon termination and muscle, such as wingless and frizzled are down regulated. Ectopic co-expression of Dimm and the insulin receptor augments most of the above effects on the motor neurons. In summary, ectopic Dimm expression alters the glutamatergic motor neuron phenotype toward a neuroendocrine one, both pre- and post-synaptically. Thus, Dimm is a key organizer of both secretory capacity and morphological features characteristic of neuroendocrine cells, and this transcription factor affects also post- synaptic proteins.

  • 8.
    Nässel, Dick R.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Kubrak, Olga I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Liu, Yiting
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Luo, Jiangnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Lushchak, Oleh V.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Factors that regulate insulin producing cells and their output in Drosophila2013Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 4, artikkel-id 252Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Insulin-like peptides (ILPs) and growth factors (IGFs) not only regulate development, growth, reproduction, metabolism, stress resistance, and lifespan, but also certain behaviors and cognitive functions. ILPs, IGFs, their tyrosine kinase receptors and downstream signaling components have been largely conserved over animal evolution. Eight ILPs have been identified in Drosophila (DILP1-8) and they display cell and stage-specific expression patterns. Only one insulin receptor, dInR, is known in Drosophila and most other invertebrates. Nevertheless, the different DILPs are independently regulated transcriptionally and appear to have distinct functions, although some functional redundancy has been revealed. This review summarizes what is known about regulation of production and release of DILPs in Drosophila with focus on insulin signaling in the daily life of the fly. Under what conditions are DILP-producing cells (IPCs) activated and which factors have been identified in control of IPC activity in larvae and adult flies? The brain IPCs that produce DILP2, 3 and 5 are indirectly targeted by DILP6 and a leptin-like factor from the fat body, as well as directly by a few neurotransmitters and neuropeptides. Serotonin, octopamine, GABA, short neuropeptide F (sNPF), corazonin and tachykinin-related peptide have been identified in Drosophila as regulators of IPCs. The GABAergic cells that inhibit IPCs and DILP release are in turn targeted by a leptin-like peptide (unpaired 2) from the fat body, and the IPC-stimulating corazonin/sNPF neurons may be targeted by gut-derived peptides. We also discuss physiological conditions under which IPC activity may be regulated, including nutritional states, stress and diapause induction.

  • 9.
    Nässel, Dick R.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Liu, Yiting
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Luo, Jiangnan
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Insulin/IGF signaling and its regulation in Drosophila2015Inngår i: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 221, s. 255-266Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Taking advantage of Drosophila as a genetically tractable experimental animal much progress has been made in our understanding of how the insulin/IGF signaling (IS) pathway regulates development, growth, metabolism, stress responses and lifespan. The role of IIS in regulation of neuronal activity and behavior has also become apparent from experiments in Drosophila. This review briefly summarizes these functional roles of IIS, and also how the insulin producing cells (IPCs) are regulated in the fly. Furthermore, we discuss functional aspects of the spatio-temporal production of eight different insulin-like peptides (DILP1-8) that are thought to act on one known receptor (dInR) in Drosophila.

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