title: Pet-1 Controls Tetrahydrobiopterin Pathway and Slc22a3 Transporter Genes in Serotonin Neurons.
abstract: Coordinated serotonin (5-HT) synthesis and reuptake depends on coexpression of Tph2, Aadc (Ddc), and Sert (Slc6a4) in brain 5-HT neurons. However, other gene products play critical roles in brain 5-HT synthesis and transport. For example, 5-HT synthesis depends on coexpression of genes encoding the enzymatic machinery necessary for the production and regeneration of tetrahydrobiopterin (BH4). In addition, the organic cation transporter 3 (Oct3, Slc22a3) functions as a low affinity, high capacity 5-HT reuptake protein in 5-HT neurons. The regulatory strategies controlling BH4 and Oct3 gene expression in 5-HT neurons have not been investigated. Our previous studies showed that Pet-1 is a critical transcription factor in a regulatory program that controls coexpression of Tph2, Aadc, and Sert in 5-HT neurons. Here, we investigate whether a common regulatory program determines global 5-HT synthesis and reuptake through coordinate transcriptional control. We show with comparative microarray profiling of flow sorted YFP(+) Pet-1(-/-) and wild type 5-HT neurons that Pet-1 regulates BH4 pathway genes, Gch1, Gchfr, and Qdpr. Thus, Pet-1 coordinates expression of all rate-limiting enzymatic (Tph2, Gch1) and post-translational regulatory (Gchfr) steps that determine the level of mammalian brain 5-HT synthesis. Moreover, Pet-1 globally controls acquisition of 5-HT reuptake in dorsal raphe 5-HT neurons by coordinating expression of Slc6a4 and Slc22a3. In situ hybridizations revealed that virtually all 5-HT neurons in the dorsal raphe depend on Pet-1 for Slc22a3 expression; similar results were obtained for Htr1a. Therefore, few if any 5-HT neurons in the dorsal raphe are resistant to loss of Pet-1 for their full neuron-type identity.
authors: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Steven C
authors: SC
authors: Wyler
authors: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Lauren J
authors: LJ
authors: Donovan
authors: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Mia
authors: M
authors: Yeager
authors: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, United States.
authors: Evan
authors: E
authors: Deneris
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D065847:Dorsal Raphe Nucleus / Q000378:metabolism*; D006136:GTP Cyclohydrolase / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D012249:Rhombencephalon / Q000378:metabolism; D059326:Serotonergic Neurons / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D000099254:Organic Cation Transporter 3
chemical_list: D001426:Bacterial Proteins; D001708:Biopterins; D002352:Carrier Proteins; D006136:GTP Cyclohydrolase; D008164:Luminescent Proteins; D027701:Organic Cation Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; D050486:Serotonin Plasma Membrane Transport Proteins; D014157:Transcription Factors; D014365:Tryptophan Hydroxylase; D000099254:Organic Cation Transporter 3; C484684:Fev protein, mouse; C000592576:GCHFR protein, mouse; C493231:Slc6a4 protein, mouse; C054562:yellow fluorescent protein, Bacteria; C487802:Tph2 protein, mouse; C000597358:Gch1 protein, mouse; C003402:sapropterin
keywords: GTP cyclohydrolase I; GTP cyclohydrolase I feedback regulator; Pet-1; Serotonin; organic cation transporter 3; quinoid dihydropteridine reductase; tetrahydrobiopterin
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