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Serotonergic neurons respond to nutrients and regulate the timing of steroid hormone biosynthesis in Drosophila.

ABSTRACT: The temporal transition of development is flexibly coordinated in the context of the nutrient environment, and this coordination is essential for organisms to increase their survival fitness and reproductive success. Steroid hormone, a key player of the juvenile-to-adult transition, is biosynthesized in a nutrient-dependent manner; however, the underlying genetic mechanism remains unclear. Here we report that the biosynthesis of insect steroid hormone, ecdysteroid, is regulated by a subset of serotonergic neurons in Drosophila melanogaster. These neurons directly innervate the prothoracic gland (PG), an ecdysteroid-producing organ and share tracts with the stomatogastric nervous system. Interestingly, the projecting neurites morphologically respond to nutrient conditions. Moreover, reduced activity of the PG-innervating neurons or of serotonin signalling in the PG strongly correlates with a delayed developmental transition. Our results suggest that serotonergic neurons form a link between the external environment and the internal endocrine system by adaptively tuning the timing of steroid hormone biosynthesis.

SUBMITTER: Shimada-Niwa Y

PROVIDER: S-EPMC4284655 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Serotonergic neurons respond to nutrients and regulate the timing of steroid hormone biosynthesis in Drosophila.

Shimada-Niwa Yuko Y Niwa Ryusuke R

Nature communications 20141215

The temporal transition of development is flexibly coordinated in the context of the nutrient environment, and this coordination is essential for organisms to increase their survival fitness and reproductive success. Steroid hormone, a key player of the juvenile-to-adult transition, is biosynthesized in a nutrient-dependent manner; however, the underlying genetic mechanism remains unclear. Here we report that the biosynthesis of insect steroid hormone, ecdysteroid, is regulated by a subset of se ...[more]

PMID: 25502946

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Project description:In insects, precisely timed periodic pulses of the molting hormone ecdysone control major developmental transitions such as molts and metamorphosis. The synthesis and release of ecdysone, a steroid hormone, is itself controlled by PTTH (prothoracicotopic hormone). PTTH transcript levels oscillate with an 8 h rhythm, but its significance regarding the timing of ecdysone pulses is unclear. PTTH acts on its target tissue, the prothoracic gland (PG), by activating the Ras/Raf/ERK pathway through its receptor Torso, however direct targets of this pathway have yet to be identified. Here, we demonstrate that Drosophila Hormone Receptor 4 (DHR4), a nuclear receptor, is a key target of the PTTH pathway and establishes temporal boundaries by terminating ecdysone pulses. Specifically, we show that DHR4 oscillates between the nucleus and cytoplasm of PG cells, and that the protein is absent from PG nuclei at developmental times when low titer ecdysone pulses occur. This oscillatory behavior is blocked when PTTH or torso function is abolished, resulting in nuclear accumulation of DHR4, while hyperactivating the PTTH pathway results in cytoplasmic retention of the protein. Increasing DHR4 levels in the PG can delay or arrest development. In contrast, reducing DHR4 function in the PG triggers accelerated development, which is caused by precocious ecdysone signaling due to a failure to repress ecdysone pulses. Finally, we show that DHR4 negatively regulates the expression of a hitherto uncharacterized cytochrome P450 gene, Cyp6t3. Disruption of Cyp6t3 function causes low ecdysteroid titers and results in heterochronic phenotypes and molting defects, indicating a novel role in the ecdysone biosynthesis pathway. We propose a model whereby nuclear DHR4 controls the duration of ecdysone pulses by negatively regulating ecdysone biosynthesis through repression of Cyp6t3, and that this repressive function is temporarily overturned via the PTTH pathway by removing DHR4 from the nuclear compartment.

Project description:Coupling immunity and development is essential to ensure survival despite changing internal conditions in the organism. Drosophila metamorphosis represents a striking example of drastic and systemic physiological changes that need to be integrated with the innate immune system. However, nothing is known about the mechanisms that coordinate development and immune cell activity in the transition from larva to adult. Here, we reveal that regulation of macrophage-like cells (hemocytes) by the steroid hormone ecdysone is essential for an effective innate immune response over metamorphosis. Although it is generally accepted that steroid hormones impact immunity in mammals, their action on monocytes (e.g. macrophages and neutrophils) is still not well understood. Here in a simpler model system, we used an approach that allows in vivo, cell autonomous analysis of hormonal regulation of innate immune cells, by combining genetic manipulation with flow cytometry, high-resolution time-lapse imaging and tissue-specific transcriptomic analysis. We show that in response to ecdysone, hemocytes rapidly upregulate actin dynamics, motility and phagocytosis of apoptotic corpses, and acquire the ability to chemotax to damaged epithelia. Most importantly, individuals lacking ecdysone-activated hemocytes are defective in bacterial phagocytosis and are fatally susceptible to infection by bacteria ingested at larval stages, despite the normal systemic and local production of antimicrobial peptides. This decrease in survival is comparable to the one observed in pupae lacking immune cells altogether, indicating that ecdysone-regulation is essential for hemocyte immune functions and survival after infection. Microarray analysis of hemocytes revealed a large set of genes regulated at metamorphosis by EcR signaling, among which many are known to function in cell motility, cell shape or phagocytosis. This study demonstrates an important role for steroid hormone regulation of immunity in vivo in Drosophila, and paves the way for genetic dissection of the mechanisms at work behind steroid regulation of innate immune cells.

Project description:BackgroundDrosophila larval locomotion consists of forward peristalsis interrupted by episodes of pausing, turning and exploratory behavior (head swinging). This behavior can be regulated by visual input as seen by light-induced increase in pausing, head swinging and direction change as well as reduction of linear speed that characterizes the larval photophobic response. During 3rd instar stage, Drosophila larvae gradually cease to be repelled by light and are photoneutral by the time they wander in search for a place to undergo metamorphosis. Thus, Drosophila larval photobehavior can be used to study control of locomotion.ResultsWe used targeted neuronal silencing to assess the role of candidate neurons in the regulation of larval photobehavior. Inactivation of DOPA decarboxylase (Ddc) neurons increases the response to light throughout larval development, including during the later stages of the 3rd instar characterized by photoneutral response. Increased response to light is characterized by increase in light-induced direction change and associated pause, and reduction of linear movement. Amongst Ddc neurons, suppression of the activity of corazonergic and serotonergic but not dopaminergic neurons increases the photophobic response observed during 3rd instar stage. Silencing of serotonergic neurons does not disrupt larval locomotion or the response to mechanical stimuli. Reduced serotonin (5-hydroxytryptamine, 5-HT) signaling within serotonergic neurons recapitulates the results obtained with targeted neuronal silencing. Ablation of serotonergic cells in the ventral nerve cord (VNC) does not affect the larval response to light. Similarly, disruption of serotonergic projections that contact the photoreceptor termini in the brain hemispheres does not impact the larval response to light. Finally, pan-neural over-expression of 5-HT1A Dro receptors, but not of any other 5-HT receptor subtype, causes a significant decrease in the response to light of 3rd instar larvae.ConclusionOur data demonstrate that activity of serotonergic and corazonergic neurons contribute to the control of larval locomotion by light. We conclude that this control is carried out by 5-HT neurons located in the brain hemispheres, but does not appear to occur at the photoreceptor level and may be mediated by 5-HT1A Dro receptors. These findings provide new insights into the function of 5-HT neurons in Drosophila larval behavior as well as into the mechanisms underlying regulation of larval response to light.

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Serotonergic neurons respond to nutrients and regulate the timing of steroid hormone biosynthesis in Drosophila.

Publications

Serotonergic neurons respond to nutrients and regulate the timing of steroid hormone biosynthesis in Drosophila.

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