Hepatocyte growth factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons

• Published in: The Journal of neuroscience 2010-09, Vol.30 (37), p.12414-12423
• Main Authors: Gascon, Eduardo, Gaillard, Stéphane, Malapert, Pascale, Liu, Yang, Rodat-Despoix, Lise, Samokhvalov, Igor M, Delmas, Patrick, Helmbacher, Françoise, Maina, Flavio, Moqrich, Aziz
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biochemistry, Molecular Biology; Cell Differentiation; Cell Differentiation - physiology; Cell Lineage; Cell Lineage - physiology; Cells, Cultured; Core Binding Factor Alpha 2 Subunit; Core Binding Factor Alpha 2 Subunit - antagonists & inhibitors; Core Binding Factor Alpha 2 Subunit - biosynthesis; Core Binding Factor Alpha 2 Subunit - physiology; Ganglia, Spinal; Ganglia, Spinal - cytology; Ganglia, Spinal - growth & development; Ganglia, Spinal - metabolism; Hepatocyte Growth Factor; Hepatocyte Growth Factor - physiology; Life Sciences; Mice; Mice, Knockout; Mice, Transgenic; Models, Neurological; Neuropeptides; Neuropeptides - physiology; Nociceptors; Nociceptors - cytology; Nociceptors - metabolism; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins c-met - deficiency; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - physiology; Signal Transduction; Signal Transduction - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3135-10.2010

Nociceptors in peripheral ganglia display a remarkable functional heterogeneity. They can be divided into the following two major classes: peptidergic and nonpeptidergic neurons. Although RUNX1 has been shown to play a pivotal role in the specification of nonpeptidergic neurons, the mechanisms driving peptidergic differentiation remain elusive. Here, we show that hepatocyte growth factor (HGF)-Met signaling acts synergistically with nerve growth factor-tyrosine kinase receptor A to promote peptidergic identity in a subset of prospective nociceptors. We provide in vivo evidence that a population of peptidergic neurons, derived from the RUNX1 lineage, require Met activity for the proper extinction of Runx1 and optimal activation of CGRP (calcitonin gene-related peptide). Moreover, we show that RUNX1 in turn represses Met expression in nonpeptidergic neurons, revealing a bidirectional cross talk between Met and RUNX1. Together, our novel findings support a model in which peptidergic versus nonpeptidergic specification depends on a balance between HGF-Met signaling and Runx1 extinction/maintenance.