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| Status |
Public on Jan 08, 2016 |
| Title |
Pet-1 Switches Transcriptional Targets Postnatally to Regulate Maturation of Serotonin Neuron Excitability. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Newborn neurons enter an extended maturation stage, during which they acquire excitability characteristics crucial for development of presynaptic and postsynaptic connectivity. In contrast to earlier specification programs, little is known aboutthe regulatory mechanisms that control neuronal maturation. The Pet-1 ETS (E26 transformation-specific) factor is continuously expressed in serotonin (5-HT) neurons and initially acts in postmitotic precursors to control acquisition of 5-HT transmitter identity. Using a combination of RNA sequencing, electrophysiology, and conditional targeting approaches, we determined gene expression patterns in maturing flow-sorted 5-HT neurons and the temporal requirements for Pet-1 in shaping these patterns for functional maturation of mouse 5-HT neurons. We report a profound disruption of postmitotic expression trajectories in Pet-1 / neurons, which prevented postnatal maturation of 5-HT neuron passive and active intrinsic membrane properties, G-protein signaling, and synaptic responses to glutamatergic, lysophosphatidic, and adrenergic agonists. Unexpectedly, conditional targeting revealed a postnatal stage-specific switch in Pet-1 targets from 5-HT synthesis genes to transmitter receptor genes required for afferent modulation of 5-HT neuron excitability. 5-HT1a autoreceptor expression depended transiently on Pet-1, thus revealing an early postnatal sensitive period for control of 5-HT excitability genes. Chromatin immunoprecipitation followed by sequencing revealed that Pet-1 regulates 5-HT neuron maturation through direct gene activation and repression. Moreover, Pet-1 directly regulates the 5-HT neuron maturation factor Engrailed 1, which suggests Pet-1 orchestrates maturationthrough secondary postmitotic regulatoryfactors. The early postnatal switch in Pet-1targets uncovers a distinct neonatal stage-specific function for Pet-1, during which it promotes maturation of 5-HT neuron excitability.
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| Overall design |
5-HT neuron mRNA profiles of E11.5, E15.5, and postnatal (P1-P3) wild type (WT) and Pet-1-/- mice were generated by deep sequencing, in triplicate, using Illumina HiSeq 2500. Myc-tagged Pet-1 ChIP-seq was performed on E12.5 to E14.5 hindbrains and sequencing using NextSeq 500.
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| Contributor(s) |
Wyler SC, Spencer WC, Green NH, Rood BD, Crawford L, Craige C, Gresch P, McMahon DG, Beck SG, Deneris ES |
| Citation(s) |
26843655 |
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| Submission date |
Oct 23, 2015 |
| Last update date |
May 15, 2019 |
| Contact name |
Evan Deneris |
| E-mail(s) |
esd@case.edu
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| Organization name |
Case Western Reserve University
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| Department |
Neurosciences
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| Street address |
2109 Adelbert Rd.
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| City |
Cleveland |
| State/province |
OH |
| ZIP/Postal code |
44106 |
| Country |
USA |
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| Platforms (2) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (20)
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| Relations |
| BioProject |
PRJNA299652 |
| SRA |
SRP065187 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE74315_Gene_expression_trajectories_E11.5_E15.5_PN.cuffdiff.txt.gz |
1.5 Mb |
(ftp)(http) |
TXT |
| GSE74315_Gene_expression_trajectories_E11.5_E15.5_PN.matrix.txt.gz |
783.4 Kb |
(ftp)(http) |
TXT |
| GSE74315_WT_vs_Pet1KO_5-HT_neuron_E15.5C_Clontech_cuffdiff.txt.gz |
784.0 Kb |
(ftp)(http) |
TXT |
| GSE74315_WT_vs_Pet1KO_5-HT_neuron_E15.5N_NuGen_cuffdiff.txt.gz |
781.1 Kb |
(ftp)(http) |
TXT |
| GSE74315_mycPet-1_ChIP_peaks.mm10.bed.gz |
72.8 Kb |
(ftp)(http) |
BED |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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