Hepatocyte growth factor acts as a motogen and guidance signal for gonadotropin hormone-releasing hormone-1 neuronal migration.
Reproduction in mammals is under the control of the hypothalamic neuropeptide gonadotropin hormone-releasing hormone-1 (GnRH-1). GnRH-1-secreting neurons originate during embryonic development in the nasal placode and migrate into the forebrain along olfactory nerves. Gradients of secreted molecules may play a role in this migratory process. In this context, hepatocyte growth factor (HGF) is a potential candidate, because it promotes cell motility in developing brain and has been shown previously to act as a motogen on immortalized GnRH-1 neurons (GN11). In this study, the role of HGF and its receptor Met during development of the GnRH-1 system was examined. GnRH-1 cells express Met during their migration and downregulate its expression once they complete this process. Tissue-type plasminogen activator (tPA), a known HGF activator, is also detected in migratory GnRH-1 neurons. Consistent with in vivo expression, HGF is present in nasal explants, and GnRH-1 neurons express Met. HGF-neutralizing antibody was applied to explants to examine the role of the endogenous growth factor. Migration of GnRH-1 cells and olfactory axon outgrowth were significantly reduced, in line with disruption of a guidance gradient. Exogenous application of HGF to explants increased the distance that GnRH-1 cells migrated, suggesting that HGF also acts as a motogen to GnRH-1 neurons. Functional experiments, performed on organotypic slice cultures, show that creation of an opposing HGF gradient inhibits GnRH-1 neuronal migration. Finally, tPA(-/-):uPA(-/-) (urokinase-type plasminogen activator(-/-)) knock-out mice exhibit strong reduction of the GnRH-1 cell population. Together, these data indicate that HGF signaling via Met receptor influences the development of GnRH-1.
Giacobini
Paolo
P
Department of Human and Animal Biology, University of Torino, 10123 Torino, Italy. paolo.giacobini@unito.it
Messina
Andrea
A
Wray
Susan
S
Giampietro
Costanza
C
Crepaldi
Tiziana
T
Carmeliet
Peter
P
Fasolo
Aldo
A
D000818:Animals; D002460:Cell Line; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000502:physiology*; D004285:Dogs; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D009924:Organ Culture Techniques; D011247:Pregnancy; D011498:Protein Precursors / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D011498:Protein Precursors; C050866:progonadoliberin I; D007987:Gonadotropin-Releasing Hormone; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met