Hepatocyte growth factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons.
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.
Gascon
Eduardo
E
Institut de Biologie du Développement de Marseille Luminy, Unite Mixte de Recherche 6216, Centre National de la Recherche Scientifique-Université de la Méditerranée, 13288 Marseille, France.
Gaillard
Stéphane
S
Malapert
Pascale
P
Liu
Yang
Y
Rodat-Despoix
Lise
L
Samokhvalov
Igor M
IM
Delmas
Patrick
P
Helmbacher
Françoise
F
Maina
Flavio
F
Moqrich
Aziz
A
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008959:Models, Neurological; D009479:Neuropeptides / Q000502:physiology; D009619:Nociceptors / Q000166:cytology / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D050676:Core Binding Factor Alpha 2 Subunit; D009479:Neuropeptides; C493726:Runx1 protein, mouse; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met