Extrinsic and intrinsic signals converge on the Runx1/CBFβ transcription factor for nonpeptidergic nociceptor maturation

Abstract
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Abstract

The generation of diverse neuronal subtypes involves specification of neural progenitors and, subsequently, postmitotic neuronal differentiation, a relatively poorly understood process. Here, we describe a mechanism whereby the neurotrophic factor NGF and the transcription factor Runx1 coordinate postmitotic differentiation of nonpeptidergic nociceptors, a major nociceptor subtype. We show that the integrity of a Runx1/CBFβ holocomplex is crucial for NGF-dependent nonpeptidergic nociceptor maturation. NGF signals through the ERK/MAPK pathway to promote expression of Cbfb but not Runx1 prior to maturation of nonpeptidergic nociceptors. In contrast, transcriptional initiation of Runx1 in nonpeptidergic nociceptor precursors is dependent on the homeodomain transcription factor Islet1, which is largely dispensable for Cbfb expression. Thus, an NGF/TrkA-MAPK-CBFβ pathway converges with Islet1-Runx1 signaling to promote Runx1/CBFβ holocomplex formation and nonpeptidergic nociceptor maturation. Convergence of extrinsic and intrinsic signals to control heterodimeric transcription factor complex formation provides a robust mechanism for postmitotic neuronal subtype specification.

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Author details

Siyi Huang

Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States

Competing interests
No competing interests declared.
Kevin J O'Donovan

Burke Medical Research Institute, Weill Cornell Medical College, White Plains, United States

Competing interests
No competing interests declared.
Eric E Turner

Seattle Children's Hospital, Seattle Children's Research Institute, Seattle Children's, Seattle, United States

Competing interests
No competing interests declared.
Jian Zhong

Burke Medical Research Institute, Weill Cornell Medical College, White Plains, United States

Competing interests
No competing interests declared.
David D Ginty

Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States

For correspondence
david_ginty@hms.harvard.edu

Competing interests
David D Ginty, Reviewing editor, eLife.

Reviewing Editor

Ben Barres, Stanford School of Medicine, United States

Ethics

Animal experimentation: This study was done in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Johns Hopkins University School of Medicine. The protocols were approved by the Animal Care and Use Committee of the Johns Hopkins University School of Medicine (Protocol Numbers: MO11M10).

Version history

Received: August 14, 2015
Accepted: September 28, 2015
Accepted Manuscript published: September 29, 2015 (version 1)
Version of Record published: November 15, 2015 (version 2)

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.