Hepatocyte Growth Factor-Met Signaling Is Required forRunx1Extinction and Peptidergic Differentiation in Primary Nociceptive Neurons

Abstract

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.

Pool-Specific Regulation of Motor Neuron Survival by Neurotrophic Support

“…This switch in function according to the developmental stage that we report here is reminiscent of our studies on dorsal root ganglion sensory neurons. Whereas at E12.5, Met regulates survival of a subpopulation of sensory neurons expressing the TrkA receptor (Maina et al, 1997), this trophic dependency is lost at later stages (Gascon et al, 2010). Instead, after birth, HGF/Met acts synergistically with nerve growth factor (NGF)/ TrkA to promote expression of the peptidergic characteristics of a subset of nociceptive neurons (Gascon et al, 2010), through crossrepressive regulatory interactions with Runx1, in contrast to the positive regulation we report in MNs.…”

“…Whereas at E12.5, Met regulates survival of a subpopulation of sensory neurons expressing the TrkA receptor (Maina et al, 1997), this trophic dependency is lost at later stages (Gascon et al, 2010). Instead, after birth, HGF/Met acts synergistically with nerve growth factor (NGF)/ TrkA to promote expression of the peptidergic characteristics of a subset of nociceptive neurons (Gascon et al, 2010), through crossrepressive regulatory interactions with Runx1, in contrast to the positive regulation we report in MNs. Other neurotrophic factors may also contribute to maintenance of MN numbers after the period of naturally occurring cell death (Baudet et al, 2008;Lee et al, 2008).…”

Hepatocyte Growth Factor and MET Support Mouse Enteric Nervous System Development, the Peristaltic Response, and Intestinal Epithelial Proliferation in Response to Injury

“…We also note that CRE-induced MET mutations are not restricted to the ENS in Met cKO mice (Danielian et al, 1998). MET should be disrupted in CGRP-expressing DRG neurons (Gascon et al, 2010) that might normally enhance mucosal repair (Takami et al, 2009;Engel et al, 2011Engel et al, , 2012Lee et al, 2012). MET inactivation in vagal neurons (Freem et al, 2010) could also increase severity of DSS-induced injury (Mazelin et al, 1999;Ghia et al, 2006Ghia et al, , 2007Van Der Zanden et al, 2009) since some vagal nuclei express Met (Caton et al, 2000;Wu and Levitt, 2013).…”

“…For example, stretch opens IPAN gadolinium-insensitive mechanosensitive ion channels (Kunze et al, 1999), whereas mucosal deformation triggers serotonin and ATP release from enteroendocrine cells to activate IPAN 5HT 3 /5HT 4 or P2X receptors (Grider and Jin, 1994; Pan and Raybould et al, 2004;Patel, 2014 (Gascon et al, 2010). Nonetheless, in contrast to in vitro results, whole-bowel transit, gastric emptying, small-bowel transit, and colonic-bead expulsion were normal in vivo in Met cKO mice.…”

The transcription factor c-Maf in sensory neuron development

“…For instance, diversification and maturation of nociceptors start around E15.5 and are only completed after birth and depend on the neurotrophin NGF, the transcription factor Runx1 and the tyrosine kinase receptor Met. [11][12][13] Compared with nociceptors, mechanoreceptor mature faster. 14 The developmental mechanisms that generate the functional and anatomical diversity of sensory neurons are incompletely understood.…”