Egfr Signaling Is a Major Regulator of Ecdysone Biosynthesis in the Drosophila Prothoracic Gland

Abstract

Understanding the mechanisms that determine final body size of animals is a central question in biology. In animals with determinate growth, such as mammals or insects, the size at which the immature organism transforms into the adult defines the final body size, as adult individuals do not grow [1Gokhale R.H. Shingleton A.W. Size control: the developmental physiology of body and organ size regulation.Wiley Interdiscip. Rev. Dev. Biol. 2015; 4: 335-356Crossref PubMed Scopus (46) Google Scholar]. In Drosophila, the growth period ends when the immature larva undergoes the metamorphic transition to develop the mature adult [2Rewitz K.F. Yamanaka N. O’Connor M.B. Developmental checkpoints and feedback circuits time insect maturation.Curr. Top. Dev. Biol. 2013; 103: 1-33Crossref PubMed Scopus (82) Google Scholar]. This metamorphic transition is triggered by a sharp increase of the steroid ecdysone, synthetized in the prothoracic gland (PG), that occurs at the end of the third instar larvae (L3) [3Truman J.W. Riddiford L.M. Endocrine insights into the evolution of metamorphosis in insects.Annu. Rev. Entomol. 2002; 47: 467-500Crossref PubMed Scopus (293) Google Scholar, 4Truman J.W. Riddiford L.M. The morphostatic actions of juvenile hormone.Insect Biochem. Mol. Biol. 2007; 37: 761-770Crossref PubMed Scopus (80) Google Scholar, 5Yamanaka N. Rewitz K.F. O’Connor M.B. Ecdysone control of developmental transitions: lessons from Drosophila research.Annu. Rev. Entomol. 2013; 58: 497-516Crossref PubMed Scopus (325) Google Scholar, 6Hiruma K. Kaneko Y. Hormonal regulation of insect metamorphosis with special reference to juvenile hormone biosynthesis.Curr. Top. Dev. Biol. 2013; 103: 73-100Crossref PubMed Scopus (56) Google Scholar]. It is widely accepted that ecdysone biosynthesis in Drosophila is mainly induced by the activation of tyrosine kinase (RTK) Torso by the prothoracicotropic hormone (Ptth) produced into two pairs of neurosecretory cells that project their axons onto the PG [7Gilbert L.I. Rybczynski R. Warren J.T. Control and biochemical nature of the ecdysteroidogenic pathway.Annu. Rev. Entomol. 2002; 47: 883-916Crossref PubMed Scopus (374) Google Scholar, 8McBrayer Z. Ono H. Shimell M. Parvy J.-P. Beckstead R.B. Warren J.T. Thummel C.S. Dauphin-Villemant C. Gilbert L.I. O’Connor M.B. Prothoracicotropic hormone regulates developmental timing and body size in Drosophila.Dev. Cell. 2007; 13: 857-871Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar]. However, the fact that neither Ptth nor torso-null mutant animals arrest larval development but only present a delay in the larva-pupa transition [9Rewitz K.F. Yamanaka N. Gilbert L.I. O’Connor M.B. The insect neuropeptide PTTH activates receptor tyrosine kinase torso to initiate metamorphosis.Science. 2009; 326: 1403-1405Crossref PubMed Scopus (201) Google Scholar, 10Grillo M. Furriols M. de Miguel C. Franch-Marro X. Casanova J. Conserved and divergent elements in Torso RTK activation in Drosophila development.Sci. Rep. 2012; 2: 762Crossref PubMed Scopus (29) Google Scholar, 11Shimell M. Pan X. Martín F.A. Ghosh A.C. Léopold P. O’Connor M.B. Romero N.M. Prothoracicotropic hormone modulates environmental adaptive plasticity through the control of developmental timing.Development. 2018; 145: dev159699Crossref PubMed Scopus (27) Google Scholar] mandates for a reconsideration of the conventional model. Here, we show that Egfr signaling, rather than Ptth/torso, is the major contributor of ecdysone biosynthesis in Drosophila. We found that Egfr signaling is activated in the PG in an autocrine mode by the EGF ligands spitz and vein, which in turn are regulated by the levels of ecdysone. This regulatory positive feedback loop ensures the production of ecdysone to trigger metamorphosis by a progressive Egfr-dependent activation of MAPK/ERK pathway, thus determining the animal final body size.

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