Genomic Decoding of Neuronal Depolarization by Stimulus-Specific NPAS4 Heterodimers

Cells regulate gene expression in response to salient external stimuli. In neurons, depolarization leads to the expression of inducible transcription factors (ITFs) that direct subsequent gene regulation. Depolarization encodes both a neuron's action potential (AP) output and synaptic inputs, v...

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Bibliographic Details
Published inCell Vol. 179; no. 2; pp. 373 - 391.e27
Main Authors Brigidi, G Stefano, Hayes, Michael G B, Delos Santos, Nathaniel P, Hartzell, Andrea L, Texari, Lorane, Lin, Pei-Ann, Bartlett, Anna, Ecker, Joseph R, Benner, Christopher, Heinz, Sven, Bloodgood, Brenda L
Format Journal Article
LanguageEnglish
Published United States 03.10.2019
Subjects
3' Untranslated Regions
Action Potentials
Animals
Basic Helix-Loop-Helix Transcription Factors - genetics
Basic Helix-Loop-Helix Transcription Factors - metabolism
CA1 Region, Hippocampal - cytology
CA1 Region, Hippocampal - metabolism
CA1 Region, Hippocampal - physiology
Cells, Cultured
Excitatory Postsynaptic Potentials
Female
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Neurons - metabolism
Neurons - physiology
Protein Multimerization
Rats
Rats, Sprague-Dawley
RNA, Messenger - genetics
RNA, Messenger - metabolism
Transcriptional Activation
NPAS4
ARNT2
CRISPR Cas9
genome
hippocampus
ARNT
dendrite
immediate early gene
inducible transcription factor
local translation
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Summary:Cells regulate gene expression in response to salient external stimuli. In neurons, depolarization leads to the expression of inducible transcription factors (ITFs) that direct subsequent gene regulation. Depolarization encodes both a neuron's action potential (AP) output and synaptic inputs, via excitatory postsynaptic potentials (EPSPs). However, it is unclear if distinct types of electrical activity can be transformed by an ITF into distinct modes of genomic regulation. Here, we show that APs and EPSPs in mouse hippocampal neurons trigger two spatially segregated and molecularly distinct induction mechanisms that lead to the expression of the ITF NPAS4. These two pathways culminate in the formation of stimulus-specific NPAS4 heterodimers that exhibit distinct DNA binding patterns. Thus, NPAS4 differentially communicates increases in a neuron's spiking output and synaptic inputs to the nucleus, enabling gene regulation to be tailored to the type of depolarizing activity along the somato-dendritic axis of a neuron.
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AUTHOR CONTRIBUTIONS
G.S.B. and B.L.B. conceived of the study, designed the experiments, and co-wrote the manuscript. G.S.B. performed electrophysiology, immunohistochemistry, in situ hybridization, biochemistry, and ChIP- and RNA-seq experiments, conducted data analysis, and assembled figures. M.G.B.H. conducted ChIP-seq experiments and analysis. N.P.D.S performed ChIP- and RNA-seq analysis. A.L.H. performed electrophysiology, immunohistochemistry, and data analysis. P-A.L. performed immunohistochemistry and data analysis. L.T. contributed methodological assistance with ChIP-seq, and conducted analysis. A.B. and J.R.E. assisted with sequencing analysis. S.H. and C.B. designed and supervised ChIP-seq experiments and analysis.
ISSN:1097-4172
0092-8674
1097-4172
DOI:10.1016/j.cell.2019.09.004