Hepatocyte Growth Factor Regulates Migration of Olfactory Interneuron Precursors in the Rostral Migratory Stream through Met-Grb2 Coupling

Abstract

The olfactory bulb is one of the few structures in the mammalian forebrain in which continuous neurogenesis takes place throughout life. Neuronal precursors originate from progenitors located in the subventricular zone (SVZ) of the lateral ventricles, move tangentially in chains through the rostral migratory stream (RMS), and reach the olfactory bulb (OB), where they finally differentiate into granule and glomerular interneurons. Multiple molecular factors are involved in controlling the various steps of this neurogenic process. Here, we show that hepatocyte growth factor (HGF) and its receptor Met protein are expressed in vivo in the OB and throughout the migratory pathway, implying that HGF might mediate migratory signals in this system. By using primary in vitro cultures, we demonstrate that HGF promotes migration of RMS neuroblasts, acting both as an inducer and attractant. HGF stimulation on RMS tissue explants selectively induces MAP kinase pathway activation. Furthermore, in vitro analysis of mice with a point mutation in the Met receptor that impairs signal transduction through the Ras/MAP kinase pathway (Met Grb2/Grb2 ) shows that without Met-Grb2 binding, neuroblast migration is reduced. Overall, these findings indicate that HGF signaling via Met-Grb2 coupling influences olfactory interneuron precursor migration along the RMS.

Mechanisms of Neurogenesis in the Normal and Injured Adult Brain

“…49,50 Other growth/trophic factors such as hepatocyte growth factor, brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor, and Netrin-1 also show attractant activity for neuroblasts in vitro, although in vivo evidence for their involvement remains to be demonstrated. [51][52][53][54] In the RMS, neuroblasts move inside the glial tube, which is reported to support their long-distance cell migration through intercellular molecular interactions. For example, the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) secreted by migrating neuroblasts is taken up by the RMS astrocytes, leading to negative regulation of the migration speed.…”

Quiescent neuronal progenitors are activated in the juvenile guinea pig lateral striatum and give rise to transient neurons

“…Tissue explant cultures were performed as described by Garzotto et al (2008). Briefly, brains were dissected out and cut by Vibratome into 250 μm thick coronal slices.…”

Endogenous Expression of Matriptase in Neural Progenitor Cells Promotes Cell Migration and Neuron Differentiation

“…HGF was previously shown to be involved in interneuron (42) and striatal progenitor cell (43) migration. It was recently shown that HGF promotes migration of rostral migratory stream neuroblasts (44) and that HGF is the factor secreted by glioma to attract neural progenitor cells (45). We asked whether MTP is also involved in NP cell migration stimulated by these factors.…”