Hepatocyte growth factor regulates migration of olfactory interneuron precursors in the rostral migratory stream through Met-Grb2 coupling.
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.
Department of Animal and Human Biology, University of Turin, 10123 Turin, Italy. donatella.garzotto@unito.it
Donatella
D
Garzotto
Paolo
P
Giacobini
Tiziana
T
Crepaldi
Aldo
A
Fasolo
Silvia
S
De Marchis
D000818:Animals; D000831:Animals, Newborn; D002464:Cell Migration Inhibition / Q000502:physiology*; D002478:Cells, Cultured; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D007395:Interneurons / Q000166:cytology / Q000502:physiology*; D020547:Lateral Ventricles / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009830:Olfactory Bulb / Q000166:cytology / Q000378:metabolism*; D017354:Point Mutation; D011485:Protein Binding / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met