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Cell. 2019 Oct 3;179(2):373-391.e27. doi: 10.1016/j.cell.2019.09.004.

Genomic Decoding of Neuronal Depolarization by Stimulus-Specific NPAS4 Heterodimers.

Author information

1
Division of Biological Sciences, Section of Neurobiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0634, USA.
2
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0634, USA.
3
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0634, USA; Department of Biomedical Informatics, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0634, USA.
4
Division of Biological Sciences, Section of Neurobiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0634, USA; Neuroscience Graduate Program, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0634, USA.
5
Genomic Analysis Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
6
Genomic Analysis Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, La Jolla, CA 92093, USA.
7
Division of Biological Sciences, Section of Neurobiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0634, USA. Electronic address: blbloodgood@ucsd.edu.

Abstract

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.

KEYWORDS:

ARNT; ARNT2; CRISPR Cas9; NPAS4; dendrite; genome; hippocampus; immediate early gene; inducible transcription factor; local translation

PMID:
31585079
DOI:
10.1016/j.cell.2019.09.004

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