title: Nutritional control of body size through FoxO-Ultraspiracle mediated ecdysone biosynthesis.
abstract: Despite their fundamental importance for body size regulation, the mechanisms that stop growth are poorly understood. In Drosophila melanogaster, growth ceases in response to a peak of the molting hormone ecdysone that coincides with a nutrition-dependent checkpoint, critical weight. Previous studies indicate that insulin/insulin-like growth factor signaling (IIS)/Target of Rapamycin (TOR) signaling in the prothoracic glands (PGs) regulates ecdysone biosynthesis and critical weight. Here we elucidate a mechanism through which this occurs. We show that Forkhead Box class O (FoxO), a negative regulator of IIS/TOR, directly interacts with Ultraspiracle (Usp), part of the ecdysone receptor. While overexpressing FoxO in the PGs delays ecdysone biosynthesis and critical weight, disrupting FoxO-Usp binding reduces these delays. Further, feeding ecdysone to larvae eliminates the effects of critical weight. Thus, nutrition controls ecdysone biosynthesis partially via FoxO-Usp prior to critical weight, ensuring that growth only stops once larvae have achieved a target nutritional status.
authors.affiliation: Development, Evolution and the Environment Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Takashi
authors.initials: T
authors.lastname: Koyama
authors.affiliation: Development, Evolution and the Environment Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Marisa A
authors.initials: MA
authors.lastname: Rodrigues
authors.affiliation: Protein-Nucleic Acids Interactions Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Alekos
authors.initials: A
authors.lastname: Athanasiadis
authors.affiliation: Department of Biology, Lake Forest College, Lake Forest, United States.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Shingleton
authors.affiliation: Development, Evolution and the Environment Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Christen K
authors.identifier: http://orcid.org/0000-0002-9765-4021
authors.initials: CK
authors.lastname: Mirth
mesh_terms: D000595:Amino Acid Sequence; D000824:Animal Nutritional Physiological Phenomena; D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D049628:Body Size / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology* / Q000235:genetics / Q000378:metabolism*; D004440:Ecdysone / Q000096:biosynthesis*; D005247:Feeding Behavior; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007328:Insulin / Q000378:metabolism; D007814:Larva / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D011485:Protein Binding; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism; D013217:Starvation; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D007328:Insulin; D013002:Somatomedins; D014157:Transcription Factors; C066030:USP protein, Drosophila; D004440:Ecdysone
keywords: D. melanogaster; body size; critical weight; developmental biology; ecdysone; insulin/insulin-like growth factor; nutrition-dependent signaling; stem cells; target of rapamycin