Coordination Among Multiple Receptor Tyrosine Kinase Signals ControlsDrosophilaDevelopmental Timing and Body Size

Abstract

Body size and the timing of metamorphosis are two important interlinked life-history traits that define holometabolous insect development. Metamorphic timing is largely controlled by a neuroendocrine signaling axis composed of the prothoracic gland (PG) and its presynaptic neurons (PGNs). The PGNs produce prothoracicotropic hormone (PTTH) that stimulates the PG to produce the metamorphosis inducing hormone ecdysone (E) through activation of Torso a Receptor tyrosine kinase the Receptor Tyrosine kinase and its downstream Ras/Erk signal transducers. Here we identify two additional timing signals produced by the RTKs Anaplastic lymphoma kinase (Alk) and the PDGF/VEGF-receptor related (PvR), Similar to Torso, both Alk and PvR trigger Ras/Erk signaling in the PG to up regulate expression of E biosynthetic enzymes, while Alk also suppresses autophagy induction after critical weight by activating Pi3K/Akt. When overexpressed, both RTKs hyperactivate an endogenous low-level Jak/Stat signal in the PG resulting in developmental delay or arrest. The Alk ligand Jelly belly (Jeb) is produced by the PGNs, and together with PTTH serves as a second PGN derived tropic factor that stimulates E production by the PG. In addition, we find that Pvf3, a PvR ligand, is also produced by the PGNs, but we show that the activation of PvR primarily relies on autocrine signaling by PG-derived Pvf2 and Pvf3. These findings illustrate that a multitude of juxtracrine and autocrine signaling systems have evolved to regulate the timing of metamorphosis, the defining event of holometabolous development.

Intrinsic and tumor-induced JAK/STAT signaling regulate developmental timing by the Drosophila prothoracic gland

“…Our results show that JAK/STAT signaling is active in the PG at low levels during normal development. Another study examined JAK/STAT activity in the PG and found in it as well expression of the same 10xSTAT-GFP reporter we used (Pan and O'Connor, 2020). We found, in addition, that pupation is slightly advanced and the size of the ring gland is smaller in multiple conditions of JAK/STAT signaling reduction, including knock down in PG cells of upd3, which a GAL4 expression reporter shows is intrinsically expressed in the ring gland.…”

A local insulin reservoir ensures developmental progression in condition of nutrient shortage in Drosophila

“…Indeed, IIS activation could prevent starvation-induced autophagy in PG cells, which has been shown to block ecdysone production in condition of a pre-NRC starvation, by shunting cholesterol away from the biosynthetic pathway (Pan, Neufeld, & O’Connor, 2019). Recent evidence suggests that alternative nutrient-independent growth factors such as Jelly-belly (Jeb) can also act on PG cells to stimulate IIS and ecdysone production (Pan & O’Connor, 2020). Jeb and Dilps could constitute separate inputs on ecdysone production, explaining why removal of CC Dilps only affects acceleration upon nutrient restriction but does not delay pupariation.…”

Regulation of ecdysone production in Drosophila by neuropeptides and peptide hormones

“…In addition, flies that bear a null mutation for PTTH show delayed development, but are still viable [ 66 ]. In a recent study two additional peptides, jelly belly ( jeb ) and PDGF- and VEGF-related factor 3 ( pvf3 ), were shown to be expressed in PTTH-producing neurons [ 77 ]. When the individual receptors for jeb and pvf3 are knocked down in the PG, animals exhibit a mild developmental delay and increased body size [ 77 ].…”

“…In a recent study two additional peptides, jelly belly ( jeb ) and PDGF- and VEGF-related factor 3 ( pvf3 ), were shown to be expressed in PTTH-producing neurons [ 77 ]. When the individual receptors for jeb and pvf3 are knocked down in the PG, animals exhibit a mild developmental delay and increased body size [ 77 ]. Interestingly, when the receptors for both jeb and pvf3 are knocked down in the PG in a ptth null mutant background, the developmental delay is more prolonged, and there is a larger increase in body size than in animals where only the individual receptors for jeb and pvf3 have been knocked down in the PG [ 77 ].…”

“…When the individual receptors for jeb and pvf3 are knocked down in the PG, animals exhibit a mild developmental delay and increased body size [ 77 ]. Interestingly, when the receptors for both jeb and pvf3 are knocked down in the PG in a ptth null mutant background, the developmental delay is more prolonged, and there is a larger increase in body size than in animals where only the individual receptors for jeb and pvf3 have been knocked down in the PG [ 77 ]. This suggests that Jeb and Pvf3 signalling interact with PTTH signalling in the PG to positively regulate ecdysone production.…”