InteractiveFly: GeneBrief

SIFamide: Biological Overview | References

Gene name - SIFamide

Synonyms -

Cytological map position - 60D5-60D5

Function - secreted neuropeptide

Keywords - hormone, regulation of feeding behavior and sexual behavior, brain

Symbol - SIFa

FlyBase ID: FBgn0053527

Genetic map position - chr2R:24,577,566-24,578,143

NCBI classification - neuropeptide

Cellular location - secreted

NCBI link: EntrezGene

SIFa orthologs: Biolitmine
Recent literature
Huang, H., Possidente, D. R. and Vecsey, C. G. (2021). Optogenetic activation of SIFamide (SIFa) neurons induces a complex sleep-promoting effect in the fruit fly Drosophila melanogaster. Physiol Behav 239: 113507. PubMed ID: 34175361
Sleep is a universal and extremely complicated function. Sleep is regulated by two systems-sleep homeostasis and circadian rhythms. In a wide range of species, neuropeptides have been found to play a crucial role in the communication and synchronization between different components of both systems. In the fruit fly Drosophila melanogaster, SIFamide (SIFa) is a neuropeptide that has been reported to be expressed in 4 neurons in the pars intercerebralis (PI) area of the brain. Previous work has shown that transgenic ablation of SIFa neurons, mutation of SIFa itself, or knockdown of SIFa receptors reduces sleep, suggesting that SIFa is sleep-promoting. However, those were all constitutive manipulations that could have affected development or resulted in compensation, so the role of SIFa signaling in sleep regulation during adulthood remains unclear. This study, examined the sleep-promoting effect of SIFa through an optogenetic approach, which allowed for neuronal activation with high temporal resolution, while leaving development unaffected. Activation of the red-light sensor Chrimson in SIFa neurons was found to promote sleep in flies in a sexually dimorphic manner, where the magnitude of the sleep effect was greater in females than in males. Because neuropeptidergic neurons often also release other transmitters, RNA interference was used to knock down SIFa while also optogenetically activating SIFa neurons. SIFa knockdown only partially reduced the magnitude of the sleep effect, suggesting that release of other transmitters may contribute to the sleep induction when SIFa neurons are activated. Video-based analysis showed that activation of SIFa neurons for as brief a period as 1 second was able to decrease walking behavior for minutes after the stimulus. Future studies should aim to identify the transmitters that are utilized by SIFa neurons and characterize their upstream activators and downstream targets. It would also be of interest to determine how acute optogenetic activation of SIFa neurons alters other behaviors that have been linked to SIFa, such as mating and feeding.

Animal behavior is, on the one hand, controlled by neuronal circuits that integrate external sensory stimuli and induce appropriate motor responses. On the other hand, stimulus-evoked or internally generated behavior can be influenced by motivational conditions, e.g., the metabolic state. Motivational states are determined by physiological parameters whose homeostatic imbalances are signaled to and processed within the brain, often mediated by modulatory peptides. This study investigate the regulation of appetitive and feeding behavior in the fruit fly, Drosophila melanogaster. Four neurons in the fly brain that release SIFamide were found to be integral elements of a complex neuropeptide network that regulates feeding. SIFamidergic cells integrate feeding stimulating (orexigenic) and feeding suppressant (anorexigenic) signals to appropriately sensitize sensory circuits, promote appetitive behavior, and enhance food intake. This study advances the cellular dissection of evolutionarily conserved signaling pathways that convert peripheral metabolic signals into feeding-related behavior (Martelli, 2017).

Animals have interlaced neuronal and endocrine systems to control feeding behavior by integrating internal information about metabolic needs and external stimuli signaling the availability and quality of nutrition. In mammals, various internal sensors monitor the metabolic state and convey endocrine and neuronal signals to peripheral organs and the brain, e.g., through the release of peptides, such as leptin, ghrelin, insulin, and peptide YY, or through the neuronal activity of the sensory vagus nerve afferents. The hypothalamus (HT) represents a main integrator of these signals and contains neuronal circuits regulating energy homeostasis. Antagonistically acting populations of neurons in the arcuate nucleus that express neuropeptide Y (NPY), agouti-related peptide (AgRP), peptides derived from the precursors pro-opiomelanocortin (POMC), or cocaine- and amphetamine-regulated transcript (CART), respectively, integrate these peripheral signals. Activating NPY/AgRP-releasing and orexin-releasing neurons, or injection of these peptides, enhances food intake, whereas activating POMC- and CART-expressing neurons or injection of these peptides decreases it. How exactly these peptides modulate neuronal circuits that control feeding-related behavior remains unclear (Martelli, 2017).

The brain of the fruit fly, Drosophila melanogaster, is much simpler in terms of cell numbers when compared to the mammalian brain. Its often individually identifiable neurons can be genetically targeted and manipulated or monitored using DNA-encoded Ca2+ sensors. Feeding-related behavior ranging from odor-guided foraging to food uptake has been exceedingly well described in Drosophila and other flies. Neural circuits controlling distinct aspects of feeding, e.g., the detection of gustatory and olfactory food stimuli, internal sensing of hemolymph sugar concentration, motor control of proboscis extension, food intake, and feeding-induced suppression of alternative behaviors like locomotion, have been characterized. Also in flies, peptidergic neurons modulate feeding behavior. The release of short neuropeptide F (sNPF) increases appetitive odor-guided behavior and food uptake. Conversely, drosulfakinin/, a cholecystokinin homolog, allatostatin A (AstA), and myosin inhibitory peptide (MIP) reduce food intake. However, a function for the neuropeptide SIFamide in feeding-related behavior remains unclear. The SIFamide amino acid sequence is largely conserved across the arthropod lineage (Verleyen, 2004) and has been implicated in courtship behavior and sleep in Drosophila (Terhzaz, 2007, Park, 2014, Sellami, 2015), aggression in a freshwater prawn, as well as in various feeding-related physiological processes, e.g., the modulation of the stomatogastric ganglion in lobsters or the control of salivary glands in blood-sucking ticks. The SIFamide receptor (SIFaR) (Jørgensen, 2006) is a homolog of the vertebrate gonadotropin inhibitory hormone receptor (GnIHR), although their respective ligands, SIFamide and GnIH, are not sequence related. GnIHR regulates food intake and reproductive behavior in opposite directions, thereby promoting feeding behavior over alternative behavioral tasks in periods of metabolic needs. However, it remains unclear whether the functions of the SIFamide- and GnIH-signaling pathways, respectively, are conserved across phyla (Martelli, 2017).

This study used Drosophila to study the role of SIFamide in feeding behavior. Thermogenetic activation of SIFamidergic neurons was shown to enhance appetitive behavior evoked by gustatory and olfactory stimuli, as well as food intake. Second, it was shown that release of SIFamide sensitizes olfactory signaling in the antennal lobe (AL). Third, it was demonstrated that orexigenic as well as anorexigenic peptidergic neurons interact anatomically and functionally with SIFamidergic cells in the brain. These findings together identify SIFamide neurons as an interface between intrinsic metabolic signals and sensory neuronal circuits mediating appetitive behavior and food intake (Martelli, 2017).

A circadian output center controlling feeding:fasting rhythms in Drosophila

Circadian rhythms allow animals to coordinate behavioral and physiological processes with respect to one another and to synchronize these processes to external environmental cycles. In most animals, circadian rhythms are produced by core clock neurons in the brain that generate and transmit time-of-day signals to downstream tissues, driving overt rhythms. The neuronal pathways controlling clock outputs, however, are not well understood. Furthermore, it is unclear how the central clock modulates multiple distinct circadian outputs. Identifying the cellular components and neuronal circuitry underlying circadian regulation is increasingly recognized as a critical step in the effort to address health pathologies linked to circadian disruption, including heart disease and metabolic disorders. Building on the conserved components of circadian and metabolic systems in mammals and Drosophila melanogaster, this study used a recently developed feeding monitor to characterize the contribution to circadian feeding rhythms of two key neuronal populations in the Drosophila pars intercerebralis (PI; the central neuroendocrine system), which is functionally homologous to the mammalian hypothalamus. Thermogenetic manipulations of PI neurons expressing the neuropeptide SIFamide (SIFa) as well as mutations of the SIFa gene degrade feeding:fasting rhythms. In contrast, manipulations of a nearby population of PI neurons that express the Drosophila insulin-like peptides (DILPs) affect total food consumption but leave feeding rhythms intact. The distinct contribution of these two PI cell populations to feeding is accompanied by vastly different neuronal connectivity as determined by trans-Tango synaptic mapping. These results for the first time identify a non-clock cell neuronal population in Drosophila that regulates feeding rhythms and furthermore demonstrate dissociable control of circadian and homeostatic aspects of feeding regulation by molecularly-defined neurons in a putative circadian output hub (Dreyer, 2019).

At its core, the circadian system is made up of central clock neurons in the brain that keep time through the presence of cell-autonomous molecular clocks. To enact behavioral rhythms, these clock cells must be connected through output pathways to downstream neuronal populations that directly control behavioral outputs; therefore, a complete understanding of circadian regulation of behavior depends on the delineation of output circuitry. This study identified a population of SIFa+ neurons in the pars intercerebralis that comprises part of the output pathway controlling feeding:fasting rhythms in flies. Constitutive activation of these cells strongly compromises normal patterns of feeding behavior, including producing a substantial percentage of flies that feed arrhythmically. This study also pinpointed a specific contribution of SIFa peptide to feeding rhythms, as SIFa mutant and RNAi knockdown lines show similar reductions of feeding rhythm strength (Dreyer, 2019).

The identification of a neuronal population and associated signaling molecule for the control of feeding:fasting rhythms should facilitate future studies aimed at further dissecting feeding output circuits, with the ultimate aim of tracing the pathway to motor neurons that directly control feeding. To that end, the trans-Tango analysis demonstrated that many neurons throughout the brain are postsynaptic to SIFa+ PI cells, including in areas such as the AL, which is involved in olfactory processing, and the SEZ, which is involved in gustatory processing and also contains feeding-related motor neurons. It will be of interest to more definitively determine the functional and neurochemical identity of postsynaptic neurons and to assess whether manipulations of SIFa receptor expression in these putative downstream output cells can recapitulate the feeding phenotypes observed following SIFa+ cell manipulations (Dreyer, 2019).

A role for SIFa in feeding regulation is supported by a recent study that demonstrated that SIFa modulates olfactory processing under conditions of starvation. Flies normally show sensitized AL projection neuron responses to food odors following starvation, however, this sensitization is absent in flies in which SIFa expression has been reduced through RNAi mechanisms. Martelli (2017) also showed that SIFa+ cells exhibit increased activity in response to starvation, and that thermogenetic activation of SIFa+ cells increases food consumption in satiated flies. Their experiments suggest that SIFa tunes sensory responsiveness to food cues according to the energy status of the fly, which subsequently increases feeding propensity in energy-depleted states. The described effects in this study identify an additional function of SIFa in dictating temporal patterns of feeding (Dreyer, 2019).

Interestingly, although the current findings of increased food consumption following SIFa+ cell activation are in line with those of Martelli (2017), this study found that feeding amount was also elevated in SIFa mutant flies, which is not predicted by a model in which SIFa peptide solely serves to increase appetitive and feeding behavior. This suggests that the exact nature of the regulation of feeding by SIFa is complex and may vary depending on environmental conditions and internal state. It is unclear why food consumption would be similarly affected by manipulations that eliminate SIFa peptide and those that hyperactivate SIFa+ cells, which should result in heightened SIFa signaling. One possibility is that constitutive SIFa+ cell activity could ultimately deplete SIFa stores, thus mimicking the SIFa mutant phenotype. Alternatively, feeding phenotypes may be affected differentially by SIFa mutations, which are present throughout development, compared to adult-specific thermogenetic activation. Regardless of whether acute SIFa signaling stimulates or inhibits food consumption, the fact that SIFa+ cell activation and reduction of SIFa signaling via mutations, cell ablation, or RNAi knockdown consistently degrade feeding:fasting rhythms provides strong evidence for a central contribution to the determination of the timing of feeding (Dreyer, 2019).

Flies in which SIFa+ cells are constitutively activated or that lack SIFa peptide due to cellular ablation or mutation also exhibit significantly reduced rest:activity rhythms, which is consistent with previous results demonstrating weakened locomotor rhythms following ablation of these cells. This effect was most pronounced in SIFa>reaper flies, indicating a potential for additional neurotransmitters emanating from SIFa+ cells to contribute to the regulation of locomotor activity. The overlap of feeding:fasting and rest:activity disruption raises the question of whether SIFa cells independently regulate feeding and locomotor rhythms, or whether one of these is indirectly affected secondary to changes in the other. Feeding and locomotor activity are interconnected behaviors that usually coincide, as animals primarily feed during their active phase. Nevertheless, feeding and locomotor rhythms can be dissociated in both flies and mammals. For example, adipocyte-specific knockout of the mammalian clock gene Arntl attenuates feeding rhythms in mice while leaving rest:activity rhythms intact, and mutations in mammalian per1 and per2 genes have differential effects on the phasing of locomotor and feeding rhythms. A similar phenotype has been noted in flies, as cell-specific abrogation of the molecular clock in the Drosophila fat body, a peripheral metabolic tissue, selectively alters the phase and magnitude of feeding rhythms without changing cycles of rest and activity (Xu, 2008). More recently, it was shown that manipulations that downregulate DH44 signaling or silence neurons expressing the hugin peptide significantly degrade rest:activity rhythm strength in DD conditions but leave the strength of DD feeding:fasting intact. Taken together, these results confirm that feeding:fasting rhythms are under de facto circadian control and do not simply occur secondary to rest:activity rhythms. Because locomotor rhythm disruption can occur independent of changes in feeding behavior, it is concluded that the effects of the SIFa manipulations likely reflect direct feeding:fasting rhythm regulation (Dreyer, 2019).

In addition to affecting rest:activity and feeding:fasting rhythms, adult-specific SIFa+ cell manipulations also resulted in high lethality, particularly in the case of adult-specific neuronal silencing. This suggests that SIFa+ cells perform some necessary function in the adult animal, though it seems that SIFa peptide itself is dispensable for survival, as mutants eclose at expected Mendelian ratios. Intriguingly, it was found that a substantial number of flies eclosed from genetic crosses that result in SIFa+ cell ablation during developmental stages due to expression of the apoptotic gene reaper. The lack of a lethality phenotype in SIFa+ ablated flies is perhaps due to compensatory changes in these flies that are not present following adult-specific manipulations. It is unclear whether the lethality phenotype is related to alterations in feeding behavior following SIFa+ cell manipulations, or whether other, yet unidentified contributions of SIFa+ cells are responsible, but as there is little evidence for SIFa expression in cells outside of the PI, it is likely that the phenotype stems from dysregulation of these cells (Dreyer, 2019).

Together with previous findings, the current results add to a growing understanding of the PI in the control of circadian outputs. The PI is situated in a region of the Drosophila brain that is near the axon terminals of multiple groups of core clock cells, and previous work has shown anatomical and functional connections between clock cells and multiple PI populations, including those expressing DH44, SIFa and DILPs. These clock cell inputs could allow PI cells, which lack molecular clocks, to transmit circadian information to downstream output regions. Interestingly, the PI cell populations appear to differentially contribute to circadian outputs. As detailed above, DH44+ cells selectively regulate rest:activity rhythms while SIFa+ cells contribute to both rest:activity and feeding:fasting rhythms. DILP+ PI cells contribute to neither behavioral rhythm but instead have been shown to modulate circadian gene expression in the fat body. These results support the hypothesis that the PI is a circadian output hub that channels core clock input into anatomically distinct output pathways to coordinately regulate different circadian outputs (Dreyer, 2019).

Though no effect of DILP+ cell manipulations on feeding:fasting rhythms were observed, changes in overall food intake following IPC activation were observed in two independent assays, which is consistent with a homeostatic role for these cells. The IPCs receive feedback from a range of circulating peptides and are also indirectly targeted by satiety signals secreted from the fat body integrating information regarding the nutritional status of a fly as one component of the intricate regulation of energy homeostasis. DILP+ neurons have also recently been shown to play a role in nutrient sensing in female flies, contributing to the modulation of reproductive dormancy by affecting overall feeding and maintaining females in a metabolically active state. Generally, IPC neuronal activity is regulated by feeding status, as the cells are more active in the fed versus starved state, which likely results in increased DILP secretion in fed flies. In turn, insulin/IGF signaling (IIS) is an integral regulator of growth and development and affects a range of physiological attributes including metabolism, reproduction, stress response, and aging (Dreyer, 2019).

DILPs have also been directly implicated in regulating feeding behavior, with several studies demonstrating anorexigenic effects of increased DILP signaling, as well as of drosulfakinin peptides, which are an additional output of the IPCs and act as a satiety signal. These effects are in line with evidence demonstrating increased activation of IPCs and release of DILPs in the fed state. In contrast, it has also been shown that DILP+ cell silencing can result in hypophagia, as indicated by reduced fecal output, and that thermogenetic DILP+ cell activation can either stimulate or inhibit feeding depending on metabolic status. Thus, the role of the DILP+ PI cells in determining overall food consumption, similar to SIFa peptides, is likely complex. Given this, the finding of increased feeding following IPC stimulation, though counterintuitive, is not without precedent, and may occur as a result of an interaction between diet type, insulin signaling, and the metabolic condition of the flies, especially as they are exposed to a carbohydrate-only diet in the FLIC and CAFE assays. Alternatively, increased feeding could occur if DILPs are depleted by extended IPC activation. This possibility could be directly tested using recently-developed DILP2 reporter flies, which allow for sensitive measurements of circulating DILP2 levels (Dreyer, 2019).

The contrasting effects of DILP+ and SIFa+ PI cell activation demonstrate dissociable control over homeostatic and circadian regulation of feeding by these two populations of PI cells. The results of the trans-Tango analyses provide a potential anatomical basis for this and suggest that DILP+ and SIFa+ PI cells rely on different signaling paradigms. Given their limited connectivity to other brain regions, the IPCs likely release DILPs systemically to act on target tissues, including the brain, via long-distance diffusion through the hemolymph. In contrast, SIFamidergic cells appear to act via direct synaptic connections to impact widespread brain areas. The differences in kinetics between these two signaling mechanisms could underlie the functional differences of these cell populations with respect to feeding regulation, with IPC activity reflecting overall energy status and therefore controlling homeostatic aspects of feeding, and SIFa cells regulating moment-to-moment feeding decisions and therefore controlling circadian patterns of feeding. In addition, the downstream connections of SIFa+ cells to central clock neurons, including l-LNvs and s-LNvs as well as LNds, implicates SIFa+ cells in feedback control of the central clock. Previous work found no alterations in central clock timing following SIFa+ cell ablation; however, as SIFa+ cells appear to lie at a crossroads of energetic signaling, it follows that they would have the capacity to relay that information back to the core clock and affect behavioral changes that are attuned to the circadian patterns of activity as necessary, perhaps under conditions in which food access is limited (Dreyer, 2019).

Research into metabolic and feeding control continues to uncover a dense web of interconnected regulators, indicative of how integral proper nutrient signaling is to overall organismal health. The partial reduction of feeding rhythm strength ascribed to SIFa here leaves room for the discovery of additional signals affecting circadian feeding rhythms. Two promising neuropeptides that have been shown to affect feeding behaviors are short neuropeptide F and allatostatin A, both of which also have been associated with sleep regulation in flies. Characterizing the complete output circuit of circadian feeding behavior in flies will help identify the most important contributors to synchronized feeding patterns and increase understanding of the profound metabolic consequences of circadian disruption (Dreyer, 2019).

SIFamide acts on fruitless neurons to modulate sexual behavior in Drosophila melanogaster

The Drosophila gene fruitless expresses male and female specific transcription factors which are responsible for the generation of male specific neuronal circuitry for courtship behavior. Mutations in this gene may lead to bisexual behavior in males. Bisexual behavior in males also occurs in the absence of the neuropeptide SIFamide. SIFamide neurons do not express fruitless. However, when fruitless neurons are made to express RNAi specific for the SIFamide receptor, male flies engage in bisexual behavior, showing that SIFamide acts on fruitless neurons. If neurons expressing a SIFaR-gal4 transgene are killed by the apoptotic protein Reaper or when these neurons express SIFamide receptor RNAi, males also show male-male courtship behavior. This transgene was used to localize neurons that express the SIFamide receptor. Such neurons are ubiquitously present in the central nervous, and two neurons were also found in the uterus that project into the central nervous system (Sellami, 2015).

SIFamide and SIFamide receptor defines a novel neuropeptide signaling to promote sleep in Drosophila

SIFamide receptor (SIFR) is a Drosophila G protein-coupled receptor for the neuropeptide SIFamide (SIFa). Although the sequence and spatial expression of SIFa are evolutionarily conserved among insect species, the physiological function of SIFa/SIFR signaling remains elusive. This study provides genetic evidence that SIFa and SIFR promote sleep in Drosophila. Either genetic ablation of SIFa-expressing neurons in the pars intercerebralis (PI) or pan-neuronal depletion of SIFa expression shortened baseline sleep and reduced sleep-bout length, suggesting that it caused sleep fragmentation. Consistently, RNA interference-mediated knockdown of SIFR expression caused short sleep phenotypes as observed in SIFa-ablated or depleted flies. Using a panel of neuron-specific Gal4 drivers, SIFR effects were further mapped to subsets of PI neurons. Taken together, these results reveal a novel physiological role of the neuropeptide SIFa/SIFR pathway to regulate sleep through sleep-promoting neural circuits in the PI of adult fly brains (Park 2014).

This study provides new evidence that the neuropeptide SIFa and its G protein-coupled receptor SIFR are novel mediators for promoting sleep in Drosophila. Either genetic ablation of SIFa-expressing neurons or depletion of SIFa expression shortened baseline sleep and caused sleep fragmentation by decreasing sleep-bout length. Consistent with these observations, a recent study independently revealed a possible sleep promoting role of SIFa-expressing neurons in DD conditions (Shang, 2013). Using neuron-specific SIFR depletion, this study further mapped the sleep-promoting SIFR function to Dilp2-negative, SIFR-positive PI neurons (Park 2014).

The PI in adult fly brain is homologous to the mammalian hypothalamus, the control center for neurotransmitter regulation. Several therapeutic targets for human sleep disorders are concentrated in the hypothalamus. For instance, dopaminergic neurons blocked by amphetamine-like drugs induce wake-promoting signals to cure narcolepsy. Benzodiazepine compounds increase gamma-aminobutryic acid (GABA)ergic neuronal transmission to enhance sleep-promoting signals to treat insomnia. Octopamine, which is similar to mammalian norepinephrine, has been identified as a wake-promoting molecule in Drosophila. When octopamine biosynthesis is compromised, flies exhibit enhanced sleep. On the other hand, octopamine promotes wakefulness in flies, particularly at night. Moreover, octopamine and OAMB, an octopamine receptor, act in Dilp2-expressing PI neurons to promote wakefulness through the cyclic AMP (cAMP) pathway. This is in contrast with the current finding that Dilp2-negative PI neurons are important for SIFR-dependent sleep promotion. Therefore, this study has defined a novel PI circuit that promotes sleep via the SIFa-SIFR signaling pathway (Park 2014).

Additional genes have been identified as sleep regulators in the PI region of adult fly brain, including members of the rhomboid family, which are integral membrane proteases and star, a transmembrane cargo receptor. They process epidermal growth factor receptor (EGFR)- activating ligands, such as spitz, gurken, and keren, so that extracellular signal-regulated kinase (ERK) is activated by phosphorylation. When EGFR is activated, flies exhibit excessive sleep. Interestingly, depletion of rhomboid, one of the processors for the ligand of the EGF receptor in c767-Gal4 expressing PI neurons shortened sleep. Given that SIFR and rhomboid promote sleep in the same PI neurons, it might be possible that SIFR and rhomboid function together to regulate sleep through the EGFR-ERK signaling pathway. Not much is known about the SIFR in terms of its downstream effectors and how it exerts its physiological effects. In general, GPCR activates the protein kinase A (PKA)-cAMP pathway via Gs or Ca2+ through a Gq regulator. It was recently shown that lethality in flies with SIFR knock-down is rescued by the overexpression of dSTIM, one of the key regulators of store-operated Ca2+ entry (Agrawal, 2013). Furthermore, the nuclear factor of activated T cells (NFAT), a Ca2+-activated transcription factor, is regulated by SIFR in a Schneider 2 (S2) cell-based dsRNA screening (Gwack et al., 2006), suggesting that sleep regulation by SIFR might involve Ca2+ signaling. Future studies will address which signaling pathways SIFR affects to regulate neuronal activity and sleep behavior (Park, 2014).

Molecular identification of the first SIFamide receptor

SIFamide is the short name and also the C terminus of the Drosophila neuropeptide AYRKPPFNGSIFamide. SIFamide has been isolated or predicted from various insects and crustaceans, and appears to be extremely well conserved among these arthropods. However, the function of this neuropeptide is still enigmatic. This study has identified the Drosophila gene (CG10823) coding for the SIFamide receptor. When expressed in Chinese hamster ovary cells, the receptor is only activated by Drosophila SIFamide (EC(50), 2x10-8M) and not by a library of 32 other insect neuropeptides and eight biogenic amines. Database searches revealed SIFamide receptor orthologues in the genomes from the malaria mosquito Anopheles gambiae, the silkworm Bombyx mori, the red flour beetle Tribolium castaneum, and the honey bee Apis mellifera. An alignment of the five insect SIFamide or SIFamide-like receptors showed, again, an impressive sequence conservation (67-77% amino acid sequence identities between the seven-transmembrane areas; 82-87% sequence similarities). The identification of well-conserved SIFamide receptor orthologues in all other insects with a sequenced genome, suggests that the SIFamide/receptor couple must have an essential function in arthropods. This paper is the first report on the identification of a SIFamide receptor (Jorgensen, 2006).

The neuropeptide SIFamide modulates sexual behavior in Drosophila

The expression of Drosophila neuropeptide AYRKPPFNGSIFamide (SIFamide) was shown by both immunohistology and in situ hybridization to be restricted to only four neurons of the pars intercerebralis. The role of SIFamide in adult courtship behavior in both sexes was studied using two different approaches to perturb the function of SIFamide; targeted cell ablation and RNA interference (RNAi). Elimination of SIFamide by either of these methods results in promiscuous flies; males perform vigorous and indiscriminant courtship directed at either sex, while females appear sexually hyper-receptive. These results demonstrate that SIFamide is responsible for these behavioral effects and that the four SIFamidergic neurons and arborizations play an important function in the neuronal circuitry controlling Drosophila sexual behavior (Terhzaz, 2007).

SIFamide is a highly conserved neuropeptide: a comparative study in different insect species

Neb-LFamide or AYRKPPFNGSLFamide was originally purified from the grey flesh fly Neobellieria bullata as a myotropic neuropeptide. The occurrence of this peptide and its isoforms was studied in the central nervous system of different insect species by means of whole mount fluorescence immunohistochemistry, mass spectrometry, and data mining. Both sequence and immunoreactive distribution pattern are very conserved in the studied insects. In all species and stages two pairs of immunoreactive cells were coundted in the pars intercerebralis. These cells projected axons throughout the ventral nerve cord. In the adult CNSs they formed a large number of immunoreactive varicosities as well. Mass spectrometry and data mining revealed that SIFamide exists in two isoforms: [G1]-SIFamide and [A1]-SIFamide. In addition, the SIFamide joining peptide is relatively well conserved throughout arthropod species. The conserved presence of two cysteine residues, separated by six amino acid residues, allows the formation of disulphide bridges (Verleyen, 2004).


Search PubMed for articles about Drosophila SIFamide

Agrawal, T., Sadaf, S. and Hasan, G. (2013). A genetic RNAi screen for IP(3)/Ca(2)(+) coupled GPCRs in Drosophila identifies the PdfR as a regulator of insect flight. PLoS Genet 9(10): e1003849. PubMed ID: 24098151

Dreyer, A. P., Martin, M. M., Fulgham, C. V., Jabr, D. A., Bai, L., Beshel, J. and Cavanaugh, D. J. (2019). A circadian output center controlling feeding:fasting rhythms in Drosophila. PLoS Genet 15(11): e1008478. PubMed ID: 31693685

Jorgensen, L. M., Hauser, F., Cazzamali, G., Williamson, M. and Grimmelikhuijzen, C. J. (2006). Molecular identification of the first SIFamide receptor. Biochem Biophys Res Commun 340(2): 696-701. PubMed ID: 16378592

Martelli, C., Pech, U., Kobbenbring, S., Pauls, D., Bahl, B., Sommer, M. V., Pooryasin, A., Barth, J., Arias, C. W. P., Vassiliou, C., Luna, A. J. F., Poppinga, H., Richter, F. G., Wegener, C., Fiala, A. and Riemensperger, T. (2017). SIFamide translates hunger signals into appetitive and feeding behavior in Drosophila. Cell Rep 20(2): 464-478. PubMed ID: 28700946

Xu, K., Zheng, X. and Sehgal A. (2008). Regulation of feeding and metabolism by neuronal and peripheral clocks in Drosophila. Cell Metab. 8(4):289-300. PubMed ID: 18840359

Park, S., Sonn, J. Y., Oh, Y., Lim, C. and Choe, J. (2014). SIFamide and SIFamide receptor defines a novel neuropeptide signaling to promote sleep in Drosophila. Mol Cells 37(4): 295-301. PubMed ID: 24658384

Sellami, A. and Veenstra, J. A. (2015). SIFamide acts on fruitless neurons to modulate sexual behavior in Drosophila melanogaster. Peptides 74: 50-56. PubMed ID: 26469541

Shang, Y., Donelson, N. C., Vecsey, C. G., Guo, F., Rosbash, M. and Griffith, L. C. (2013). Short neuropeptide F is a sleep-promoting inhibitory modulator. Neuron 80(1): 171-183. PubMed ID: 24094110

Terhzaz, S., Rosay, P., Goodwin, S. F. and Veenstra, J. A. (2007). The neuropeptide SIFamide modulates sexual behavior in Drosophila. Biochem Biophys Res Commun 352(2): 305-310. PubMed ID: 17126293

Verleyen, P., Huybrechts, J., Baggerman, G., Van Lommel, A., De Loof, A. and Schoofs, L. (2004). SIFamide is a highly conserved neuropeptide: a comparative study in different insect species. Biochem Biophys Res Commun 320(2): 334-341. PubMed ID: 15219831

Biological Overview

date revised: 15 April 2020

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