Control of release of dilPs from glial cells and other sources

In the above we have discussed DILP producing cells in the brain and how they may be regulated. What about DILP production/release in other cell types? It has been reported that during larval development DILP2 and 6 are expressed in glial cells of the ventral nerve cord (Chell and Brand, 2010). These glial cells are located at the surface of the ventral nerve cord, but underneath the basement membrane (i. e. inside the blood brain barrier) and are in contact with neuroblasts (neuronal stem cells). It was shown that DILPs via the dInR and PI3K reactivate these dormant neuroblasts in a nutrient dependent manner (Chell and Brand, 2010; Sousa-Nunes et al., 2011). Dilp6 transcription increases in the CNS of larvae 24h post-hatching and is dependent on amino acids in the food. Thus, for increase in DILP expression and paracrine release a nutrient-dependent signal from the fat body is required to act on the glial cells (Chell and Brand, 2010; Sousa-Nunes et al., 2011). This signal obviously has to pass through the blood-brain barrier, similar to the leptin-like Upd2 described earlier (Rajan and Perrimon, 2012).

Another case of nutrient-dependent activation of stem cells by paracrine DILP release was demonstrated in the Drosophila intestine (O'Brien et al., 2011). In the adult midgut stem cells proliferate and thus ensure growth of the intestine under good nutritional conditions. It was shown that DILP3 is expressed by muscle fibers in a region of the midgut rich in stem cells (O'Brien et al., 2011; Veenstra et al., 2008). The expression of Dilp3 transcript increases in fed flies during adult gut growth and in a temporal fashion matching the dynamics of stem cell proliferation. Experiments showed that DILP3 in the stem cell niche is necessary for proliferation and that this is dependent on nutrition (O'Brien et al., 2011). These authors propose that DILP3 production and release may depend on local nutrient sensing in the intestine, but that also circulating DILPs may provide additional activation of gut stem cells.

Finally, it was shown that principal cells of the Drosophila Malpighian tubules express DILP5 both in larvae and adults (Söderberg et al., 2011). Malpighian tubules regulate water and ion homeostasis, but may also play roles in immune responses and oxidative stress (Dow, 2009). The DILP5 levels in the principal cells are dependent on desiccation stress, but also on signaling by tachykinins (DTKs) via its receptor DTKR (Söderberg et al., 2011). Thus, DTKR is expressed in principal cells and so is the dInR. Targeted knockdown of DTKR, DILP5 or the dInR in principal cells or mutation of Dilp5 resulted in increased survival at desiccation, starvation and oxidative stress, whereas over-expression of these components produced the opposite phenotype (Söderberg et al., 2011). Therefore, various stresses seem to induce hormonal release of DTKs from the intestine that act on the renal tubules to regulate local DILP5 signaling and functions of Malpighian tubules related to overcoming oxidative stress.

Conclusions and outlook

The brain IPCs have a central role at the interface between nutritional status of the fly and control of homeostasis, physiology, and behavior. Systemic insulin signaling therefore regulates a wide array of functions in the daily life of an organism, including responses to various stresses. Importantly IPCs, and other sources of DILPs, also regulate mechanisms in growth, aging, and thereby life span. DILP signaling can be both systemic and paracrine. Systemic DILP signaling is by means of the IPCs that release DILP2, 3 and 5, or the fat body releasing DILP6 (Bai et al., 2012; Brogiolo et al., 2001; Okamoto et al., 2009; Rulifson et al., 2002; Slaidina et al., 2009). Paracrine signaling has been suggested within the brain for DILP2 from IPCs (Bader et al., 2013) and for DILP2 and 6 from glial cells to neuroblasts (Chell and Brand, 2010; Sousa-Nunes et al., 2011), for DILP3 from midgut muscle fibers to stem cells (O'Brien et al., 2011) and DILP5 acting locally in Malpighian tubules (Söderberg et al., 2011).

The IPCs also express the cholecystokinin-like peptides DSK 1 and 2 that seem to induce satiety in flies (Söderberg et al., 2012). Most likely the DILPs and DSKs act in a synchronized fashion on different targets after onset of feeding. However, the IPCs have been implicated in some activities that might not necessarily involve release of DILPs into the circulation. For instance the sleep-wake regulation by octopaminergic inputs to the IPCs (Crocker et al., 2010) could be by means of either paracrine release of DILPs into the brain or by central release of some other colocalized substance (DSK or other). Also the action of DILPs in regulation of NPF expressing neurons in feeding circuits (Wu et al., 2005a; Wu et al., 2005b) could be by means of paracrine signaling. The finding that DILP2 is taken up by identified sets of neurons in the brain, including the hugin-expressing neurons, is another example of local CNS action (Bader et al., 2013).

A somewhat puzzling feature of IPCs is that they co-express three different Dilp genes that are under individual transcriptional regulation. Different stimuli affect the transcription of these three genes in a multitude of combinations. However, most likely the depolarization of the IPCs affects release of all the peptides in whatever stoichiometric ratio they are stored. Since the DILPs 2, 3 and 5 are partly redundant functionally and only one form of dInR has been clearly identified (Brogiolo et al., 2001; Broughton et al., 2008; Grönke et al., 2010) one may wonder why the ratio between DILPs is changing. Therefore it is important to investigate whether there are several dInR subtypes or if the different DILPs have different affinities for or activities on the single known receptor.

More conclusions/questions!

Figure legends

Fig. 1. Insulin-producing cells (IPCs) in the Drosophila nervous system and gut. A set of 14 IPCs (blue) in pars intercerebralis of the brain send axons to the tritocerebrum (adjacent to the subesophageal ganglion, SEG), to the corpora cardiaca (CC) with associated aorta, proventriculus (PV), and the crop. Likely release sites for circulating Drosophila insulin-like peptides (DILPs) are in CC, aorta, PV, and crop. These IPCs produce DILP2, 3, and 5. The branches in protocerebrum (near cell bodies) and tritocerebrum of the brain could be dendritic and (or) further release sites. A second set of 20 cells (aIPCs; red) is found in the abdominal ganglion. These produce DILP7 and supply axon terminations to the hindgut including the rectal papillae (RP), and in females to reproductive organs (not shown here). At least two of the aIPCs send axons to the SEG. It is not clear whether their branches in the SEG are dendrites or release sites. Additionally the principal cells of the renal tubules (RT) produce DILP5. This DILP may act locally in the tubules. DILP6 is produced in fat body cells in the head and abdomen. The fat body also releases a leptin-like peptide, unpaired 2 (Upd

2). Both DILP6 and UPD regulate IPC activity. In the midgut there are peptidergic endocrine cells (GEC) that may release peptides into the circulation to target cells in renal tubules and brain. This figure is updated and modified from (Nässel, 2012).

Fig. 2. Insulin-producing cells (IPCs) and other neurons in the Drosophila brain. A. The IPCs are seen with their cell bodies dorsally, two sets of presumed dendrites (Dendr 1 and 2) in the pars intercerebralis and processes branching in the tritocerebrum Trito). It is not know whether these branches are dendrites or axon terminations, or both. The axons that exit to the corpora cardiaca and aorta are not displayed (they exit above the tritocerebrum, in a direction towards the reader). The antennal lobe (AL) are depicted with the anterior 10 (green and yellow) of the about 14 glomeruli that contain olfactory sensory neurons (OSNs) expressing short neuropeptide F. The yellow glomeruli are DM1 that receive OSNs expressing Or42b. The mushroom bodies with calyx (Ca), and-lobes (LL) and the lateral horn (LH) are also depicted. B. The IPCs (magenta, anti-DILP2) and corazonin-expressing (green) DLP neurons converge medially (encircled) and in the tritocerebrum (Trito). The DLPs are known to regulated IPC activity. The likely dendrites of the DLPs are indicated by arrows. B’. Detail of IPCs (enhanced color) visualizing the short dendrites (Dendr 2) that seem to receive inputs from DLPs. C. Schematic depiction of IPCs, DLPs and their point of convergence in the pars intercerebralis (Reg). For further details see Fig. 3. D. The IPCs (green) may receive inputs from serotonin-producing neuron branches (magenta) both at the long dendrites (Dendr 1) and the short (not shown here). Fig. 2B is altered from (Kapan et al., 2012) and 2D from (Luo et al., 2012).

Fig. 3. Sets of peptidergic neurons in the Drosophila brain that are associated with the IPCs. Some of the IPCs co-express drosulfakinins (DSK1 and 2), peptides that induce satiety (Söderberg et al., 2012). The IPCs are regulated by DLP neurons that produce short neuropeptide F (sNPF), corazonin (CRZ) and proctolin (Proct) (Kapan et al., 2012) as well as GABAergic neurons (GSN) that in turn receive leptin-like signals from the fat body REF. The interactions between DLPs and GSNs and IPCs probably occur dorso-medially (IDR) and maybe in the tritocerebrum (TC). Another set of neurosecretory cells (ipc-1 and ipc-2a) express the peptides sNPF, Drosophila tachykinin (DTK) and ion transport peptide (ITP) (Kahsai et al., 2010). These neurons have axon terminations in sites overlapping those of the IPCs and the DLPs in the corpora cardiaca and anterior aorta. They also react with several antisera to DILP2 (unpublished) and the insulin binding protein IMP-L2 (REF). Further abbreviations: MT, medially projecting axon tract; PLT, posterior lateral axon tract; MB, median bundle; NCC, nerves to corpora cardiaca.

Fig. 4 Summary of factors regulating IPCs.

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