Hormonal axes in Drosophila: regulation of hormone release and multiplicity of actions

Abstract

Hormones regulate development, as well as many vital processes in the daily life of an animal. Many of these hormones are peptides that act at a higher hierarchical level in the animal with roles as organizers that globally orchestrate metabolism, physiology and behavior. Peptide hormones can act on multiple peripheral targets and simultaneously convey basal states, such as metabolic status and sleep-awake or arousal across many central neuronal circuits. Thereby, they coordinate responses to changing internal and external environments. The activity of neurosecretory cells is controlled either by (1) cell autonomous sensors, or (2) by other neurons that relay signals from sensors in peripheral tissues and (3) by feedback from target cells. Thus, a hormonal signaling axis commonly comprises several components. In mammals and other vertebrates, several hormonal axes are known, such as the hypothalamic-pituitary-gonad axis or the hypothalamic-pituitary-thyroid axis that regulate reproduction and metabolism, respectively. It has been proposed that the basic organization of such hormonal axes is evolutionarily old and that cellular homologs of the hypothalamic-pituitary system can be found for instance in insects. To obtain an appreciation of the similarities between insect and vertebrate neurosecretory axes, we review the organization of neurosecretory cell systems in Drosophila. Our review outlines the major peptidergic hormonal pathways known in Drosophila and presents a set of schemes of hormonal axes and orchestrating peptidergic systems. The detailed organization of the larval and adult Drosophila neurosecretory systems displays only very basic similarities to those in other arthropods and vertebrates.

Keywords: Insect brain; Insect neurosecretory cells; Insulin signaling; Neuropeptides; Peptide hormones.

Fig. 1

Definitions of terms used in this review. The top box shows definitions and characteristics of neuropeptide and peptidergic neurons. Dimm (Dimmed) is a transcription factor that is known to specify many, especially larger, peptidergic neurons and neuroendocrine cells (Hewes et al. 2003). The lower box defines peptide hormone and neurosecretory (endocrine) cells. A given peptide can be both a neuropeptide and peptide hormone; thus, a specific GPCR can be activated by both a neuropeptide (at close range) and a peptide hormone (via circulation), probably at different EC₅₀ values. Notes: ¹Dimm expression is predominantly seen in larger neurons. ²Including neurons producing hormone release-regulating factors. ³And/or secretory cells. ⁴Muscle cells, gland cells and epithelial cells. ⁵Or other body cavities in certain invertebrates

Fig. 2

Organization of the neuroendocrine system in the fly brain compared to mammals. a Schematic of the brain and retrocerebral complex in flies. Lateral (LNC) and median (MNC) neurosecretory cell groups send their axons via a pair of nerves (nervii corpora cardiaca, NCC) to the fused CRN (cardiaca-recurrent nerve), which supplies the corpora cardiaca (CC) and hypocerebral ganglion (HG), as well as the corpora allata (CA) via the paired NCA (nervii corpora allata) nerves. Axons continue via the HG into the crop nerve (CN), which follows the crop duct (CD) and branch over the crop and an intestinal nerve (IN) that supplies branches over the proventriculus (Pro) and anterior midgut. These nerve branches contain axon terminations of the LNCs, MNCs and subesophageal zone (SEZ) neurosecretory cells and form neurohemal release sites/areas. Axon terminations from these cells are also found along the aorta. Other abbreviations: Es, esophagus; RN, recurrent nerve. The inset shows an enlarged view of the CC-CA region, indicating that both contain secretory cells producing hormones, adipokinetic hormone (AKH) and juvenile hormone (JH). The blue box indicates the area where axon terminations of LNCs and MNCs are in contact with the circulation (neurohemal area). b Frontal view of a blowfly brain where one NCC was backfilled with cobalt chloride (at the arrow) into the posterior lateral tract (PLT) and median bundle (MB). Neurosecretory cells were revealed in contralateral MNCs (MNC-c) and LNCs (LNC-c) as well as ipsilateral LNCs (LNC-i) and the SEZ. Note extensive overlapping arborizations dorsally and in tritocerebrum, Tritoc. These two figures (a, b) were redrawn and slightly altered from Shiga et al. (2000) with permission from Dr. Sakiko Shiga. Panel b appeared in a similar form in Nässel and Larhammar (2013). c Schematic of a generalized mammalian hypothalamus-pituitary. The asterisk indicates where hormone release–regulating factors enter the capillary plexus of the portal system (“neurohemal” area). Hormone-producing secretory cells are found in the anterior pituitary and the hormones released into the circulation (see text for hormones). A more detailed scheme is shown in Fig. 12

Fig. 3

Distribution of a selection of peptide hormones in neurosecretory cells in the adult Drosophila brain. (a) Schematic of some of the lateral (LNC) and median (MNC) neurosecretory cell systems in the adult fly brain. Two sets of LNCs are shown: the DLPs that produce corazonin (CRZ) and short neuropeptide F (sNPF) (Kapan et al. 2012) and the ITPn that produce ion transport peptide (ITP), sNPF and tachykinin (TK) (Kahsai et al. 2010). One set of MNCs is depicted, the insulin-producing cells (IPCs) that produce insulin-like peptides (DILP1, 2, 3 and 5) of which a subpopulation also produces sulfakinin (DSK) (Söderberg et al. 2012). A set of neuroendocrine cells (Hugin cells) in the subesophageal zone (SEZ) produces the peptide pyrokinin (Hug-PK); a subset of these constitutes neurosecretory cells (Melcher and Pankratz 2005). Axons from these four cell groups run via the median bundle (MB) or posterior lateral tract (PLT), exit the brain (at Out) via the NCC (nervii corpora cardiaca; not shown) and they reach the retrocerebral complex where axon terminations are in contact with the circulation. The DLPs utilize sNPF as a factor that regulates release of DILPs and AKH (Kapan et al. ; Oh et al. 2019) and the ITPn possibly use TK and sNPF as releasing factors and Hugin cells may employ Hug-PK to regulate release of other peptides (Schlegel et al. 2016). Interactions between the cell systems shown probably occur at the sites indicated by 1 and 2. It was shown that three of these cell types (marked with asterisks) express the protein ImpL2 and that the IPCs signal to the ITPn and Hugin cells with DILP2 via the insulin receptor in an Imp-L2-dependent fashion (Bader et al. 2013). mp, medially projecting axons of LNCs. (a’) A set of MNCs (including IPCs) reconstructed from serial electron microscopic sections of Drosophila hemibrain. d1 and d2 two sets of presumed dendrites. This figure was compiled from data in neuPRINT (https://neuprint.janelia.org) (Clements et al. ; Xu et al. ; Zheng et al. 2018). (b) There are seven pairs of CRZ expressing DLPs in pars lateralis (PL). Note that in this specimen one larger pair of cells (asterisk) is slightly dislocated medially towards pars intercerebralis (PI). (c) The DLPs (inverted image; CRZ immunolabeling, αCRZ) have axons running through the median bundle (MB) and a lateral tract (arrow). (d) The DLPs (green) impinge on the IPCs (magenta) in encircled areas 1 and 2. (e, f) Details of IPCs and branches from DLPs. D1 and d2, two sets of IPC dendrites. (g) Six median neurosecretory cells producing diuretic hormone 44 (DH44) have dendrites at the arrow and axon branches in the tritocerebrum (Tr) and subesophageal zone (SEZ) rendered by Dh44-Gal4-driven GFP and antiserum to DH44. (h) Triple labeling with antisera to ITP (magenta/white), DILP2 (red) and LkR-Gal4-driven GFP (leucokinin receptor; green) reveals ITP neurons (ITPn) and IPCs. This indicates that the LkR is expressed on both ITPn and IPCs. (i–k) The IPCs express the leucokinin receptor (LkR) seen with LkR-Gal4-driven GFP and anti-DILP2. Panel (a) is updated from Nässel et al. (2013) with data from several of the papers cited above. Panel (b) is from Kubrak et al. (2016), (c–f) are from Kapan et al. (2012), (g) from Zandawala et al. (2018a) and (h–k) from Zandawala et al. (2018b), with permission from the publishers

Fig. 4

Interorgan communication: regulation of insulin-producing cells (IPCs) in Drosophila. a Scheme with factors that regulate insulin-producing cells (IPCs) in the adult brain of Drosophila. Blue arrows depict stimulatory inputs and red bars show inhibitory ones. Dashed black line indicates incompletely known mechanisms. The IPCs are also regulated by neurons in the brain (brain modulators; see panel b for details). The fat body is nutrient sensing and releases adiponectin-like polypeptide, Upd2 (unpaired-2), and DILP6 after carbohydrate intake. Adiponectin and DILP6 act directly on the IPCs. Upd2 acts (inhibitory) on GABAergic brain neurons and thereby lifts inhibition of the IPCs. Another factor FIT (female-specific independent of transformer) is a signal released from the fat body after a protein meal. The corpora cardiaca (CC), under conditions of low sugar, releases limostatin (Lst) and adipokinetic hormone (AKH) and thereby inhibits release of DILPs. The intestine has nutrient-sensing enteroendocrine cells and there is release of at least some peptide hormones into the circulation. Two gut peptides have been shown to act on IPCs, allatostatin A (AstA), and CCHamide2 (CCHa2), whereas bursicon (Burs) from the intestine acts on brain neurons, which in turn act on CC to diminish AKH production (dashed line indicates indirect action via brain). Acronyms or peptides are given in Table 1. For references to the original data, see the text. This figure is slightly modified from Nässel and Zandawala et al. (2019) with permission. b Block diagram of factors acting on IPCs and receptors expressed on these cells. The IPCs are nutrient sensing, as are peptidergic cells in the brain and fat body (asterisks). Insulin-like peptides (DILPs) released from IPCs act on CC and fat body and regulate AKH and DILP6 release, respectively. Receptor acronyms: GABA-B-R, metabotropic GABA receptor; OAMB, octopamine receptor (mushroom body); DopR1, dopamine receptor 1; 5-HT1A, serotonin receptor 1A; dInR, insulin receptor; DTKR, TK receptor; DAR2, AstA receptor 2; AdipoR, adiponectin receptor

Fig. 5

Schemes depicting hormonal axes involving insulin-producing cells (IPCs) in adult flies. Note that in this and the following figures with schematic circuits/axes, only one cell of each type is depicted for simplicity. a Adult DLP (LNC) pathway with sNPF and corazonin (CRZ) and regulation of glucose homeostasis, food search and stress responses via IPCs and AKH-producing cells (APCs). Asterisks indicate neurons/cells that are cell autonomously nutrient sensing. The DLPs in the LNC group produce CRZ and sNPF and supply axon terminations to IPCs and APCs. The DLP-derived sNPF regulates IPCs and APCs in corpora cardiaca (CC) and thereby affects glucose homeostasis and metabolic stress responses (Kapan et al. ; Oh et al. 2019), whereas CRZ is released into the circulation from the neurohemal area (NhA) associated with CC, the foregut and anterior aorta (Kubrak et al. 2016). CRZ acts on the fat body to regulate metabolic stress and homeostasis (Kubrak et al. 2016). sNPF activates IPCs to increase DILP release and inhibits the APCs to decrease AKH release and thereby affects carbohydrate homeostasis (Kapan et al. ; Oh et al. 2019). The signaling from IPCs to APCs in CC (dashed arrow) specifically in response to sNPF has not been demonstrated but DILPs do act on APCs, at least in larvae (Bader et al. 2013). AKH is also known to regulate the sensitivity of AKH receptor–expressing sweet-sensing gustatory neurons that mediate sweet taste (Bharucha et al. ; Jourjine et al. 2016). Note that it is not clear whether AKH acts on gustatory neuron processes within the SEZ or their cell body/dendrites in the periphery. Enteroendocrine cells (EECs) of the midgut release bursicon that indirectly inhibits APCs in CC resulting in decreased release of AKH and thus affect glucose homeostasis (Scopelliti et al. 2014). Another regulator of IPCs and APCs is allatostatin A (AstA) but the neuronal pathway mediating this has not been clearly shown (Hentze et al. 2015). Thus, it might be that instead of SEZ neurons, AstA is derived from gut EECs. The fat body may feed back to IPCs by means of DILP6 and other factors such as Upd2, adiponectin and CCHa2 (see Fig. 6, Ahmad et al. ; Nässel and Zandawala 2019). Finally, DILPs and AKH regulate octopamine (OA)-producing neurons (AKHRn) that express AKH and DILP receptors. These AKHRn in turn act on octopamine receptor–expressing neurons (OARn) to activate locomotion (Yu et al. 2016). Thus, AKH regulates sensitivity of taste neurons and activates locomotion to increase food search. AKH action also encompasses regulation of activity/rest, depending on time of day (Pauls et al. 2020). Ach, acetylcholine; EEC, enteroendocrine cell; b the IPCs are regulated by leucokinin (LK)-producing neurons, LHLK, in the lateral horn of the brain. The LHLKs, which are under influence of clock neurons (Cavey et al. 2016), also mediate starvation-dependent changes in sleep (Yurgel et al. 2019). The nutrient-sensing LHLKs are part of an LK system in the brain and ventral nerve cord that also regulates physiological processes such as diuresis, metabolism, and organismal activity (Zandawala et al. 2018b). c Activation of IPCs blocks reproductive diapause (i.e., blocks ovarian arrest). The clock neurons, sLNv, use sNPF and PDF to activate the IPCs, which leads to inhibition of diapause, likely due to DILP-mediated activation of vitellogenesis in fat body and egg maturation in ovaries (Nagy et al. 2019b). This probably also involves DILP stimulation of corpora allata (CA) and production of juvenile hormone (JH). Inputs to IPCs from another set of clock neurons (DN1s; not shown here) were shown in another study to regulate feeding rhythm and metabolism (Barber et al. 2016)

Fig. 6

Schemes depicting hormonal axes involving DH44-producing median neurosecretory cells (DH44n) in adult flies. a Localization of DH44 neurons (DH44n), Hugin cells, and the clock neurons DN1 and sLNv in the adult fly brain. The sLNv produce sNPF and PDF and the DN1 are heterogeneous and produce a variety of neuropeptides (see Abruzzi et al. 2017). b Block diagram depicting interactions between the neurons shown in panel a. The sLNv neurons act (via either sNPF or PDF) on DN1s to activate (substance not known) DH44 neurons that in turn act on a subset of DH44 receptor–expressing (DH44-R) Hugin cells (King et al. 2017). The Hugin cells utilize Hugin-pyrokinin (Hug-PK) and/or acetylcholine (Ach) to activate motor neuron circuits in the ventral nerve cord (VNC). This pathway regulates locomotor activity and in conjunction with SIFamide neurons also modulates feeding rhythms (Dreyer et al. ; King et al. 2017). Note that the DH44n (asterisk) are amino acid and glucose sensing (Dus et al. ; Yang et al. 2018). Novel data show that the Hugin cells receive inputs from sleep-promoting neurons of dorsal fan-shaped body (dFB) and that Hugin cells also act on sLNvs (not shown in diagram) (King et al. 2020). This circuit links homeostatic sleep drive and the circadian system. c The nutrient-sensing DH44 neurons induce feeding and defecation (excretion) (Dus et al. 2015). Hormonally released DH44 acts on DH44-R1-expressing muscles in the intestine to induce excretion. The DH44n also act on circuits in the brain regulating feeding. d In female flies, the DH44n release DH44 that acts on DH44-R1-expressing efferent neurons that innervate the uterus and thereby induces sperm release from spermatheca (Lee et al. 2015)

Fig. 7

Schemes depicting hormonal systems that regulate feeding and associated behaviors. a Distribution of cell bodies of peptidergic neuroendocrine cells in the brain of Drosophila that play roles in feeding. These are neurosecretory cells in MNC (IPC and DH44-PI) and LNC groups (ITPn and DLP) and interneurons located in distinct brain regions (LHLK, PLP, NPF, SIFa, Hugin and SELK); a few of the Hugin cells are neurosecretory cells. The neuron groups indicated with asterisks are nutrient sensing (only a subset of the DLPs) and the Hugin cells in the subesophageal zone receive gustatory inputs. The peptides released from these cells are shown in the legend in the upper left part of the figure (acronyms as in Table 1). Note that also circuits associated with the mushroom bodies (see box in panel b) are linked to some of the peptidergic systems shown and are involved in regulation of food seeking and feeding (Tsao et al. 2018). See text for literature references. b Four neurons producing SIFamide (SIFa) have arborizations that are widely spread throughout the brain. These SIFa neurons coordinate appetitive behavior but also influence mating and sleep (Dreyer et al. ; Martelli et al. ; Terhzaz et al. 2007). The SIFa neurons are under direct regulation by peptidergic satiety inputs (myoinhibitory peptide, MIP) and hunger inputs (Hugin-PK). SIFa neurons act on gustatory and olfactory sensory neurons, as well as sets of neurons expressing the transcription factor Fruitless, known to regulate sex-specific behavior. They also act on MNCs in the pars intercerebralis that signal with diuretic hormone 44 and insulins (not shown in the figure), as well as specific neuronal circuits regulating sleep. Anatomical studies (reconstitution of split-GFP) suggest that the SIFa neurons also receive inputs from neurons that play roles in feeding and metabolism that produce corazonin (CRZ), DILPs, sulfakinin (DSK) and sNPF (Martelli et al. 2017). The IPCs are in turn regulated by sNPF and several other factors shown in the gray box in the upper left. Mushroom body–associated circuits (in box) are also involved in the regulation of food seeking; sNPF and NPF act on different sets of dopaminergic (DA) neurons (PPL, PAM), which in turn act on specific sets of mushroom body output neurons (MBONs) that induce food-seeking behavior (Tsao et al. 2018). This figure is updated from Nässel et al. (2019), which was based on data from Martelli et al. (2017) and Tsao et al. (2018)

Fig. 8

Schemes depicting circuits/axes involving SIFamide- and ion transport peptide-producing interneurons (ITPn) in adult flies. (a, a’) Reconstructions of two SIFa neurons from serial electron microscopic sections (combined in the third panel, a”). MB, mushroom body, LH, lateral horn, AL, antennal lobe. The numbers identify the neurons in the database. These panels were compiled from data in neuPRINT (https://neuprint.janelia.org) (Clements et al. ; Xu et al. ; Zheng et al. 2018). (b) SIFamide (SIFa)-producing interneurons are central in regulating appetitive behavior and decreasing sleep and mating behavior. As also shown in Fig. 7, the SIFa neurons are modulated by neurons producing MIP, Hugin-PK and possibly CRZ/sNPF. The SIFa neurons also target SIFa receptor–expressing peptidergic neurons (SIFaR) in the CNS. Of these, AKH-, AstA- and LK-expressing neurons induce shorter mating duration and CAPA-, FMRFa- and DMS-expressing ones induce longer mating (Wong et al. 2019). Dashed lines indicate that actions have not been shown experimentally in the context of SIFa signaling. Peptide acronyms are as in Table 1. (c) Ion transport peptide (ITP) is produced by a set of LNCs (ITPn) that has axon terminations in corpora cardiaca (CC) and allata (CA), as well as neurohemal areas (NhA). ITP regulates water intake and water reabsorption/excretion and possibly metabolism (Galikova et al. 2018). The ITPn are targets of DILP2 from the IPCs (Bader et al. 2013) and express the LK receptor (Zandawala et al. 2018b) but the functional aspects of this are not known

Fig. 9

Schemes depicting neurosecretory and efferent neuronal systems in the adult ventral nerve cord. a, b Cell bodies of neurosecretory cells in the adult ventral nerve cord (VNC) are mainly found in abdominal neuromeres and only a set of FMRFamide-expressing cells are known in the thoracic neuromeres. The peptide acronyms are explained in Table 1. a Peptide hormones regulating water and ion balance, as well as stress responses. The Va neurons have axon terminations in a neurohemal area in the dorsal neural sheath of the VNC, the others terminate on muscles in the body wall. b Peptides with unclear functions in the adult. The Tv cells have axon terminations in a plexus forming a neurohemal area in the dorsal neural sheath of the VNC, the others terminate on muscles in the body wall. c Peptide hormones in abdominal neuromeres that regulate water and ion balance. Dashed lines indicate that actions from abdominal cells have not been shown experimentally. Some of the cells are regulated by specific substances (serotonin, DILPs and CRZ); the LK producing ABLK neurons express receptors for DILPs and serotonin (Liu et al. 2015) and the Va neurons (CAPA1 and CAPA2) express CRZ receptors (Zandawala et al. 2019). d Cells expressing bursicon (Burs) activate cuticle plasticization and cuticle tanning (indirectly via DILP7-expressing neurons, DILP7n). Bursicon regulates its own release (Peabody et al. 2008). e Efferent peptidergic neurons innervate the hindgut and/or reproductive tract. Of the neurons shown, only those expressing DILP7 and PDF (thick arrows) have been analyzed functionally (Cognigni et al. ; Talsma et al. ; Yang et al. 2008). Thus, the functions of the remaining neurons are unknown (but see text)

Fig. 10

Neurosecretory cells in CNS of larval Drosophila. (a) Schematic depiction of cell bodies of neurosecretory cells in different regions of the CNS: corpora cardiaca (CC), median neurosecretory cells (MNC), lateral neurosecretory cells (LNC), subesophageal zone (SEZ; neuromeres S1–3) and ventral nerve cord (VNC; neuromeres T1–3 and A1–9). To the right, we display a legend of the different cell types (color coded) and their peptides (in bold the cell names, in italics the peptides). Note that the ipc-1 neurons are the same as the ITPn in the adult brain. The acronyms of the peptides are given in Table 1. (b) The primary release sites of different peptidergic hormone systems. Left column shows brain-derived hormones and right column hormones from cells in the VNC. Abbreviations: CC, corpora cardiaca; PTG, prothoracic gland; Th-PVO, thoracic perivisceral organs; Abd-PVO, abdominal perivisceral organs. This figure is updated and partly redrawn from a figure in Nässel and Zandawala et al. (2019), which in turn was based on Wegener et al. (2006)

Fig. 11

Schemes depicting neurosecretory systems in the larva. a Role of prothoracicotropic hormone neurons (PTTHn) and IPCs in timing of growth and maturation of third instar (L3) larvae. Neurons producing allatostatin A (AstAn) stimulate both PTTHn and IPCs via the receptor AstAR1 (DAR1) and this leads to ecdysone (Ecd) production and DILP release, which affects timing of development and maturation. In the mid L3, Ecd blocks growth and in late L3 the Ecd peak stimulates onset of sexual maturation (Deveci et al. 2019). Another study showed that corazonin (CRZ) activates PTTHn and thus basal Ecd production and increased larval growth (Imura and Shimada-Niwa 2020) and finally it was shown that both CRZ and sNPF from DLPs are required for regulation of IPCs (and growth) under nutrient restriction (Megha et al. 2019). It is not clear whether the two peptides (CRZ and AstA) cooperate in growth regulation since they were not investigated in the same study. b The IPCs are regulated by a pair of neurons (ICN) that produce tachykinin (TK) and myoinhibitory peptide (MIP) (Meschi et al. 2019). It was shown that TK inhibits IPCs and thus growth is inhibited. The ICNs are activated by growth-blocking peptide (GBP) from the fat body in a nutrient-dependent fashion. The role of MIP was not investigated. c Insulin-like peptide 8 (DILP8) is released upon damage to imaginal discs and acts on a set of four neurons (GCL) that express the DILP8 receptor Lgr3 (Colombani et al. ; Garelli et al. ; Vallejo et al. 2015). These GCL neurons inhibit production of PTTH by PTTHn and thus decrease growth and maturation of the larva. The transmitter of GCLs is unknown. d The late L3 larvae undergo a transition from feeding to wandering stages. At this point, they also become negatively phototactic. PTTH from the PTTHn acts on the prothoracic glands (PTG), the light-sensitive Bolwig organ and peripheral sensory neurons (class IV dendritic arborization neurons; IV dan) to alter light responses and via Ecd induce wandering behavior and finally pupariation in the dark (Yamanaka et al. 2013). The inputs to the sLNvs are from rhodopsin 6–expressing photoreceptors (not shown). In other studies, it was shown that the PTTHn are regulated with sNPF by the clock neurons sLNv (Selcho et al. 2017) and by CRZ-producing DLP neurons (Imura and Shimada-Niwa 2020). However, the direct link to the light avoidance/wandering behavior and pupariation is unclear (thus dashed lines). Another light-mediated pathway (not shown here but see a similar circuit in Supplementary Fig. 3) is provided by the PTTH neurons that signal to brain neurons producing eclosion hormone (EH) whose axons descend to the VNC where they contact motor neurons (Gong et al. 2019). A recent study also suggested that the NPF receptor is expressed in the PTG and that NPF signaling negatively regulates insulin signaling in the PTG influences and thereby affects growth and developmental timing (Kannangara et al. 2019). NPF was proposed to be acting systemically after release by EECs of the gut (not shown in Fig. 11)

Fig. 12

Signaling in hypothalamus and pituitary in mammals. This scheme presents the most common factors seen in the hypothalamus-pituitary axes of mammals. The intermediate pituitary lobe (with its separate capillary network) and MSH signaling are not found in humans and many other mammals. Peptides are released from hypothalamic neuroendocrine cells into separate capillary networks. Sets of neuroendocrine cells release neuropeptides to the anterior lobe of the pituitary via capillaries in the median eminence. These peptides regulate the release of pituitary peptide hormones produced by endocrine cells of the anterior lobe (these cells are not shown). Additionally, dopamine and GABA exert influence on the endocrine cells (not shown). The posterior capillary network receives peptide hormones (oxytocin and vasopressin) from large hypothalamic neurons whose axons project to the posterior lobe of the pituitary. These peptides are released into the general circulation that transports them to distant target organs. The different hormones produced in the anterior lobe are also released into circulation and act on multiple targets. Some target organs (thyroid, adrenal and gonads) in turn produce “secondary” hormones of different kinds. Some of these hormones provide feedback to the hypothalamus. Abbreviations: GHRH, growth hormone–releasing hormone; PrRP, prolactin-releasing peptide; TRH, thyrotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; GnIH, gonadotropin-inhibiting hormone, CRH, corticotropin-releasing hormone; GH, growth hormone; TSH, thyroid-stimulating hormone; ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone; T3, triiodothyronine; T4, thyroxine; MSH, melanocyte-stimulating hormone. This figure is updated from Nässel and Larhammar (2013), with permission

Fig. 13

Comparison between mammalian neurosecretory systems and those of Drosophila. This highly schematic figure shows the key features of the brain-hypothalamus-pituitary axis in comparison with presumably analog regions in Drosophila. Same colors indicate presumed similar regions. Hypothalamus is divided into three regions (1–3) and the pituitary into anterior (a) and posterior (p) lobes. Substances indicated in blue are neuromodulators and/or release-regulating factors, those in dark red are hormones and the function of dromysosuppressin (DMS) in MNCs is not clear although the DMS-MNC cells have axons terminating together with those of the other MNCs. Arrows indicate action of the substances on cells in a region, blue C:s indicate release into general circulation and green arrows are feedback from target tissues. The regions “brain other” and “clock” are not interconnected to other regions with arrows to avoid complexity but certainly play important roles in regulating neurosecretory systems (and receive feedback from hormonal systems). We lumped together intestine and adipocytes as one set of target tissues and other targets are grouped in target tissues (these are, e.g., gonads, thyroid, adrenals and liver in mammals and gonads and muscles in Drosophila). Adipocytes in Drosophila include other fat body functions (e.g., liver-like and immune functions). Substances used as feedback are indicated by green (a–d) and are listed in the box below (GLP-1, glucagon-like peptide 1; IGF1, insulin-like growth factor 1; T3, triiodothyronine; T4, thyroxine; FIT, female-specific independent of transformer). Acronyms of other factors and hormones are as in Table 1. Other abbreviations: CC, corpora cardiaca; MNC, median neurosecretory cells; LNC, lateral neurosecretory cells; PV, proventriculus region (including aorta, crop duct, and CC)