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.
J Neurosci. 2010 Sep 15;30(37):12414-23. 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.
外周神经节中的伤害感受器表现出显著的功能异质性。它们可以分为以下两个主要类别：肽能神经元和非肽能神经元。尽管已经表明 RUNX1 在非肽能神经元的特化中起着关键作用，但驱动肽能分化的机制仍不清楚。在这里，我们表明肝细胞生长因子 (HGF)-Met 信号与神经生长因子-酪氨酸激酶受体 A 协同作用，促进一部分潜在伤害感受器中的肽能特性。我们提供了体内证据表明，源自 RUNX1 谱系的一群肽能神经元需要 Met 活性来正确地使 Runx1 失活并最佳地激活 CGRP（降钙素基因相关肽）。此外，我们表明 RUNX1 反过来抑制非肽能神经元中的 Met 表达，揭示了 Met 和 RUNX1 之间的双向交叉对话。总之，我们的新发现支持这样一种模型，即肽能与非肽能的特化取决于 HGF-Met 信号与 Runx1 失活/维持之间的平衡。
