Coordination Among Multiple Receptor Tyrosine Kinase Signals Controls <i>Drosophila</i> Developmental Timing and Body Size

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SummaryBody 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 (RTK) 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 juxtacrine and autocrine signaling systems have evolved to regulate the timing of metamorphosis, the defining event of holometabolous development.