title: Role of activating transcription factor-4 in 24-hour rhythm of serotonin transporter expression in the mouse midbrain.
abstract: Serotonin (5-HT) transporter (5-HTT) plays a key role in the control of 5-HT neuronal activity by reuptaking extracellular 5-HT from the synapse cleft. We have previously demonstrated that 5-HTT mRNA expression levels and its uptake activity in the mouse midbrain are significantly higher in the dark phase than those in the light phase. However, the molecular mechanisms of time-dependent expression of 5-HTT have not been clarified. In this study, expression of 5-HTT mRNA in the mouse midbrain showed a significant 24-h rhythm and was higher in the dark phase. Although such an oscillation was eliminated by a Clock gene mutation, CLOCK and BMAL1 did not activate 5-HTT transcription in the luciferase reporter assay. Activating transcription factor-4 (ATF4), a member of the ATF/cAMP response element (CRE)-binding protein family, is a component responsible for sustaining circadian oscillations of CRE-mediated gene expression. ATF4 significantly activated 5-HTT transcription in vitro and time dependently bound to the CRE site in the 5-HTT promoter in the mouse midbrain. In addition, mutation of the Clock gene disrupted temporal binding of ATF4 to the CRE site in the 5-HTT promoter. These results indicated that the circuit of circadian-basis molecular regulation between the clockwork system and mouse 5-HTT gene was connected by the ATF4 signaling pathway.
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan.
authors.forename: Kentarou
authors.initials: K
authors.lastname: Ushijima
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Sato
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Ogata
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D056926:CLOCK Proteins / Q000096:biosynthesis*; D002940:Circadian Rhythm / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D008636:Mesencephalon / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: C081452:Atf4 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D051701:Activating Transcription Factor 4; D056926:CLOCK Proteins; C538944:Clock protein, mouse