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Insulin-producing cells in the brain of adult Drosophila are regulated by the serotonin 5-HT1A receptor

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Abstract

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-HT1A, but not the 5-HT1B or 5-HT7 receptors, and that processes of serotonergic neurons impinge on the IPC branches. Knockdown of 5-HT1A 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-HT1A knockdown; this is accentuated by starvation. Heterozygous 5-HT1A mutant flies display the same phenotype in all assays, as seen after targeted 5-HT1A RNAi, and flies fed the 5-HT1A antagonist WAY100635 display reduced lifespan at starvation. Our findings suggest that serotonin acts on brain IPCs via the 5-HT1A receptor, thereby affecting their activity and probably insulin signaling. Thus, we have identified a second inhibitory pathway regulating IPC activity in the Drosophila brain.

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Abbreviations

5-HT:

5-hydroxytryptamine

5-HTP:

5-hydroxytryptophan

BDSC:

Bloomington Drosophila stock center

CNS:

Central nervous systems

DILP:

Drosophila insulin-like peptide

GABA:

Gamma-aminobutyric acid

GFP:

Green fluorescent protein

GIRK:

G-protein-coupled inwardly rectifying potassium channel

GPCR:

G-protein-coupled receptor

IPCs:

Insulin- producing cells

MNCs:

Median neurosecretory cells

NPF:

Neuropeptide F

NS3:

Nucleostemin 3

OAMB:

Octopamine receptor (mushroom bodies)

PCR:

Polymerase chain reaction

PKA:

Protein kinase A

RNAi:

RNA interference

sNPF:

Short neuropeptide F

VDRC:

Vienna Drosophila RNAi center

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Acknowledgments

We thank the persons and organizations listed in “Materials and methods” for flies and reagents. This study was supported by the Swedish Research Council (VR).

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Authors and Affiliations

  1. Department of Zoology, Stockholm University, Svante Arrhenius väg 18B, 10691, Stockholm, Sweden

    Jiangnan Luo & Dick R. Nässel

  2. Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Jaime Becnel & Charles D. Nichols

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  1. Jiangnan Luo
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Correspondence to Dick R. Nässel.

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18_2011_789_MOESM1_ESM.tif

S Fig. 1 The 5-TH1B and 5-HT7 receptors appear not to be expressed in IPCs. Antiserum to DILP2 (magenta) was combined with 5-HT 1B and 5-HT 7 -Gal4 driven GFP (green) in adult and larval brains of Drosophila (all images are projections of several optic sections). a. No colocalization of markers is seen in IPCs in the adult brain. Arrow points at a receptor expressing cell body distinct from the IPCs. In ai and aii the separate channels are shown. b. Also in the larval brain there is no colocalization of markers. c. In the adult brain the 5-HT7 is expressed mainly in neurons of the ellipsoid body (EB), including the lateral triangle (LTR), and not in the IPCs. d. The larval IPCs also do not express 5-HT7, although some adjacent cell bodies do so. (TIFF 6995 kb)

18_2011_789_MOESM2_ESM.tif

S. Fig. 2 The 5-HT1A receptor expression pattern closely resembles that of serotonergic branches. To reveal the relations between the 5-HT1A receptor and neurons processes releasing the ligand, we applied a monoclonal antibody to serotonin (magenta) and 5-HT 1A -Gal4 driven GFP (green). a – c. In the adult brain the match between the receptor and serotonin-immunoreactive processes is close. Note that the 5-HT1A expression may also include non-dendritic portions of the neurons where no receptor protein is located (accounting for part of the mismatch). Especially in the pars intercerebralis (PI) and ellipsoid body (EB) the matching patterns are seen. d. Expression of 5-HT1A (green) and serotonin (magenta) in the larval ventral nerve cord (total projection). Processses from the numerous 5-HT1A expressing neurons superimpose the serotonergic ones in the two columns of synaptic neuropil. The arrow indicates anterior (a) and posterior (p). e - f. Single channels showing 5-HT 1A -Gal4 driven GFP and serotonin-immunolabeling. (TIFF 8746 kb)

18_2011_789_MOESM3_ESM.tif

S Fig. 3 A different Dilp2 -Gal4 line to drive 5-HT 1A knockdown also renders flies more sensitive to starvation. Another Dilp2-Gal4 line (insertion on 3rd chromosome; [18]) was used for driving 5-HT1A-RNAi in IPCs as a control to establish that the effects seen are not caused by position of insert. As with the other Dilp2-Gal4 driver we observe that 5-HT1A-RNAi in IPCs render flies more sensitive to starvation (p<0.0001 to both controls, Log rank test, Mantel-Cox; n= 180 for each genotype; experiment in three replicates). (TIFF 243 kb)

18_2011_789_MOESM4_ESM.tif

S Fig. 4 Tests of RNAi for 5-HT 1B and 5-HT 7 receptors in IPCs indicate no effect on sensitivity to starvation. Although we have no evidence for expression of 5-HT1B and 5-HT7 receptors in IPCs of Drosophila we tested driving RNAi for the two receptor with the Dilp2-Gal4 line and exposed the different fly crosses to starvation. a. Attempted knockdown of 5-HT1B in IPCs [Dilp2-5-HT1BRi(V)] did not result in a change in survival at starvation compared to controls (p=0.8140 and p=0.4046 to the two controls, p=0.5431 between controls; n= 142-164 for the three genotypes, experiment in three replicates). This was a UAS-5-HT1BRNAi line from VDRC. b. Attempted knockdown of 5-HT7 in IPCs (Dilp2-5-HT7Ri) did not result in a change in survival at starvation compared to controls. (TIFF 2268 kb)

18_2011_789_MOESM5_ESM.tif

S Fig. 5 Knockdown of 5-HT 1A in IPCs or globally does not affect growth. Adult flies of the different genotypes were weighed at the age of 4 – 6 d to estimate growth. a. Knockdown of 5-HT1A in IPCs by Dilp2-Gal4 driven RNAi (Dilp2-5-HT1ARi) does not produce a noticable growth phenotype in male flies (ns, p=0.105 and *** p<0.001; one-way ANOVA, Tukey’s comparison; n = 120 for each genotype, experiment in three replicates). b. Weights of wild type (w1118) and 5-HT1A mutant flies (M, males and F, females) also do not differ (ns, p=0.07 for male mutant to wild type, and p=0.162 for female mutant to control; one-way ANOVA; n= 120 for each genotype and sex). (TIFF 344 kb)

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Luo, J., Becnel, J., Nichols, C.D. et al. Insulin-producing cells in the brain of adult Drosophila are regulated by the serotonin 5-HT1A receptor. Cell. Mol. Life Sci. 69, 471–484 (2012). https://doi.org/10.1007/s00018-011-0789-0

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