title: The TSC1/2 complex controls Drosophila pigmentation through TORC1-dependent regulation of catecholamine biosynthesis.
abstract: In Drosophila, the pattern of adult pigmentation is initiated during late pupal stages by the production of catecholamines DOPA and dopamine, which are converted to melanin. The pattern and degree of melanin deposition is controlled by the expression of genes such as ebony and yellow as well as by the enzymes involved in catecholamine biosynthesis. In this study, we show that the conserved TSC/TORC1 cell growth pathway controls catecholamine biosynthesis in Drosophila during pigmentation. We find that high levels of Rheb, an activator of the TORC1 complex, promote premature pigmentation in the mechanosensory bristles during pupal stages, and alter pigmentation in the cuticle of the adult fly. Disrupting either melanin synthesis by RNAi knockdown of melanogenic enzymes such as tyrosine hydroxylase (TH), or downregulating TORC1 activity by Raptor knockdown, suppresses the Rheb-dependent pigmentation phenotype in vivo. Increased Rheb activity drives pigmentation by increasing levels of TH in epidermal cells. Our findings indicate that control of pigmentation is linked to the cellular nutrient-sensing pathway by regulating levels of a critical enzyme in melanogenesis, providing further evidence that inappropriate activation of TORC1, a hallmark of the human tuberous sclerosis complex tumor syndrome disorder, can alter metabolic and differentiation pathways in unexpected ways.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Zitserman
authors.forename: Sapna
authors.initials: S
authors.lastname: Gupta
authors.forename: Warren D
authors.initials: WD
authors.lastname: Kruger
authors.forename: Magdalena
authors.initials: M
authors.lastname: Karbowniczek
authors.forename: Fabrice
authors.initials: F
authors.lastname: Roegiers
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000096:biosynthesis* / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004817:Epidermis / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008543:Melanins / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology; D009479:Neuropeptides / Q000502:physiology; D010858:Pigmentation / Q000235:genetics*; D011679:Pupa / Q000378:metabolism; D034622:RNA Interference; D000076205:Ras Homolog Enriched in Brain Protein; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: D002395:Catecholamines; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490212:Rheb protein, Drosophila; C570998:TORC1 protein complex, Drosophila; C515347:TSC1 protein, Drosophila; D014157:Transcription Factors; C117726:gig protein, Drosophila; C518293:raptor protein, Drosophila; D019893:Ribosomal Protein S6 Kinases; D020559:Monomeric GTP-Binding Proteins