title: The Circadian Clock Is a Key Driver of Steroid Hormone Production in Drosophila.
abstract: Biological clocks allow organisms to anticipate daily environmental changes such as temperature fluctuations, abundance of daylight, and nutrient availability. Many circadian-controlled physiological states are coordinated by the release of systemically acting hormones, including steroids and insulin [1-7]. Thus, hormones relay circadian outputs to target tissues, and disrupting these endocrine rhythms impairs human health by affecting sleep patterns, energy homeostasis, and immune functions [8-10]. It is largely unclear, however, whether circadian circuits control hormone levels indirectly via central timekeeping neurons or whether peripheral endocrine clocks can modulate hormone synthesis directly. We show here that perturbing the circadian clock, specifically in the major steroid hormone-producing gland of Drosophila, the prothoracic gland (PG), unexpectedly blocks larval development due to an inability to produce sufficient steroids. This is surprising, because classic circadian null mutants are viable and result in arrhythmic adults [4, 11-14]. We found that Timeless and Period, both core components of the insect clock [15], are required for transcriptional upregulation of steroid hormone-producing enzymes. Timeless couples the circadian machinery directly to the two canonical pathways that regulate steroid synthesis in insects, insulin and PTTH signaling [16], respectively. Activating insulin signaling directly modulates Timeless function, suggesting that the local clock in the PG is normally synced with systemic insulin cues. Because both PTTH and systemic insulin signaling are themselves under circadian control, we conclude that de-synchronization of a local endocrine clock with external circadian cues is the primary cause for steroid production to fail.
authors.affiliation: Department of Cell Biology, University of Alberta, 5-19 Medical Sciences Building, Edmonton, AB T6G 2H7, Canada.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Cara
authors.affiliation: Department of Biological Sciences, University of Alberta, G-504 Biological Sciences Building, Edmonton, AB T6G 2E9, Canada. Electronic address: kingjones@ualberta.ca.
authors.forename: Kirst
authors.initials: K
authors.lastname: King-Jones
mesh_terms: D000818:Animals; D057906:Circadian Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000254:growth & development / Q000502:physiology*; D007301:Insect Hormones / Q000378:metabolism*; D007814:Larva / Q000254:growth & development / Q000502:physiology; D056950:Period Circadian Proteins / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D007301:Insect Hormones; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; D013256:Steroids; C096445:tim protein, Drosophila; C009089:prothoracicotropic hormone
keywords: Clock; Cryptochrome; Cycle; GSK3; Halloween genes; PTTH; Period; TORSO; Timeless; Vrille; circadian rhythm; ecdysone; insulin signaling; prothoracic gland; ring gland; steroid hormones