Abstract
Transcriptional cascades are required for the specification of serotonin (5-HT) neurons and behaviors modulated by 5-HT. Several cascade factors are expressed throughout the lifespan, which suggests that their control of behavior might not be temporally restricted to programming normal numbers of 5-HT neurons. We used new mouse conditional targeting approaches to investigate the ongoing requirements for Pet-1 (also called Fev), a cascade factor that is required for the initiation of 5-HT synthesis, but whose expression persists into adulthood. We found that Pet-1 was required after the generation of 5-HT neurons for multiple steps in 5-HT neuron maturation, including axonal innervation of the somatosensory cortex, expression of appropriate firing properties, and the expression of the Htr1a and Htr1b autoreceptors. Pet-1 was still required in adult 5-HT neurons to preserve normal anxiety-related behaviors through direct autoregulated control of serotonergic gene expression. These findings indicate that Pet-1 is required across the lifespan of the mouse and that behavioral pathogenesis can result from both developmental and adult-onset alterations in serotonergic transcription.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
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Age Factors
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Analysis of Variance
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Animals
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Animals, Newborn
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Cell Differentiation
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Chromatin Immunoprecipitation / methods
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Estrogen Antagonists / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / metabolism
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / physiology*
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In Vitro Techniques
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Luminescent Proteins / genetics
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Male
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Maze Learning / drug effects
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Motor Activity / drug effects
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Motor Activity / genetics
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Neurons / drug effects
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Neurons / physiology*
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Patch-Clamp Techniques / methods
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Protein-Lysine 6-Oxidase / genetics
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Protein-Lysine 6-Oxidase / metabolism
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RNA, Messenger / metabolism
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Raphe Nuclei / cytology
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Raphe Nuclei / embryology
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Receptor, Serotonin, 5-HT1A / metabolism
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Receptor, Serotonin, 5-HT1B / metabolism
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Serotonin / physiology*
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Serotonin Plasma Membrane Transport Proteins / metabolism
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Serotonin Receptor Agonists / pharmacology
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Somatosensory Cortex / cytology
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Somatosensory Cortex / embryology
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Tamoxifen / pharmacology
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Tryptophan Hydroxylase / metabolism
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Xanthenes / metabolism
Substances
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Estrogen Antagonists
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Excitatory Amino Acid Antagonists
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Extracellular Matrix Proteins
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Fev protein, mouse
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Luminescent Proteins
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RNA, Messenger
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Receptor, Serotonin, 5-HT1B
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Receptor Agonists
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Slc6a4 protein, mouse
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Transcription Factors
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Xanthenes
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Tamoxifen
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Receptor, Serotonin, 5-HT1A
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Lox protein, mouse
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Serotonin
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8-Hydroxy-2-(di-n-propylamino)tetralin
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Texas red
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Tryptophan Hydroxylase
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Protein-Lysine 6-Oxidase