This application proposes a unique avenue of research aimed at the development and function of the mammalian serotonin neurotransmitter system. The research is based on our discovery of a novel ETS domain transcription factor, Pet-1, whose expression precisely marks 5-HT neurons before 5-HT appears in the hindbrain and before 5-HT neurons have begun to migrate to their adult midbrain/hindbrain positions. The discovery of a transcription fact that is specifically expressed in the mammalian 5-HT system is unprecedented. It serotonergic-specific expression pattern together with the presence of a Pet-1 DNA binding sites in human and mouse genes, which in large part defines the differentiated phenotype of 5-HI neurons, suggest that Pet-1 is a key determinant in the decision to become a 5-HT neuron. The experiments described in this application are aimed at testing this hypothesis and to exploit the provocative expression pattern of Pet-1 to control heterologous gene expression in a serotonergic-specific manner. The proposed aims are: 1) Investigate expression of Pet-1 alternative forms and expression of other ETS factors in the 5-HT system. 2) Identify a Pet genomic DNA fragment capable of controlling serotonergic-specific gene expression. 3) Investigate the transcriptional interaction of Pet-1 with the serotonin transporter (5-HTT), 5 HT1a receptor and tryptophan hydroxlase (TPH) genes. 4) Create a Pet-1 loss of function mouse and determine its phenotype. The function of the central 5-HT system is abnormal in numerous psychiatric disorders and thus this system is the target of several highly effective pharmacological agents that are used to treat these disorders. The information gained from completion of the proposed aims is likely to have significant impact on our basic understanding of the 5-HT system and may lead in the future to the creation of novel animal models for psychiatric disorders involving the 5-HT system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
3R01MH062723-05S1
Application #
7123569
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sieber, Beth-Anne
Project Start
2000-12-10
Project End
2006-02-28
Budget Start
2004-12-01
Budget End
2006-02-28
Support Year
5
Fiscal Year
2005
Total Cost
$125,020
Indirect Cost
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Deneris, Evan; Gaspar, Patricia (2018) Serotonin neuron development: shaping molecular and structural identities. Wiley Interdiscip Rev Dev Biol 7:
Spencer, William C; Deneris, Evan S (2017) Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function. Front Cell Neurosci 11:215
Carlson, Kaitlin S; Whitney, Meredith S; Gadziola, Marie A et al. (2016) Preservation of Essential Odor-Guided Behaviors and Odor-Based Reversal Learning after Targeting Adult Brain Serotonin Synthesis. eNeuro 3:
Whitney, Meredith Sorenson; Shemery, Ashley M; Yaw, Alexandra M et al. (2016) Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas. J Neurosci 36:9828-42
Wyler, Steven C; Spencer, W Clay; Green, Noah H et al. (2016) Pet-1 Switches Transcriptional Targets Postnatally to Regulate Maturation of Serotonin Neuron Excitability. J Neurosci 36:1758-74
Wyler, Steven C; Donovan, Lauren J; Yeager, Mia et al. (2015) Pet-1 Controls Tetrahydrobiopterin Pathway and Slc22a3 Transporter Genes in Serotonin Neurons. ACS Chem Neurosci 6:1198-205
Issler, Orna; Haramati, Sharon; Paul, Evan D et al. (2014) MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron 83:344-360
Spoida, Katharina; Masseck, Olivia A; Deneris, Evan S et al. (2014) Gq/5-HT2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice. Proc Natl Acad Sci U S A 111:6479-84
Ciarleglio, Christopher M; Resuehr, Holly E S; Axley, John C et al. (2014) Pet-1 deficiency alters the circadian clock and its temporal organization of behavior. PLoS One 9:e97412
Deneris, Evan S; Hobert, Oliver (2014) Maintenance of postmitotic neuronal cell identity. Nat Neurosci 17:899-907

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