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The Journal of Neuroscience, January 10, 2007, 27(2):431-445; doi:10.1523/JNEUROSCI.4979-06.2007

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Development/Plasticity/Repair
Hepatocyte Growth Factor Acts as a Motogen and Guidance Signal for Gonadotropin Hormone-Releasing Hormone-1 Neuronal Migration

Paolo Giacobini,¹ Andrea Messina,¹ Susan Wray,² Costanza Giampietro,³ Tiziana Crepaldi,⁴ Peter Carmeliet,⁵ and Aldo Fasolo¹

¹Department of Human and Animal Biology, University of Torino, 10123 Torino, Italy, ²Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, ³Italian Foundation for Cancer Research Institute of Molecular Oncology, 20139 Milan, Italy, ⁴Department of Anatomy, Pharmacology, and Forensic Medicine, University of Torino, 10125 Torino, Italy, and ⁵Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, 3000 Leuven, Belgium

Correspondence should be addressed to Dr. Paolo Giacobini, Department of Human and Animal Biology, Via Accademia Albertina 13, 10123 Torino, Italy. Email: paolo.giacobini{at}unito.it

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.

Key words: GnRH-1; LHRH; HGF; migration; olfactory system; development

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Received Sept. 12, 2006; accepted Dec. 6, 2006.

Correspondence should be addressed to Dr. Paolo Giacobini, Department of Human and Animal Biology, Via Accademia Albertina 13, 10123 Torino, Italy. Email: paolo.giacobini{at}unito.it

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				D. Garzotto, P. Giacobini, T. Crepaldi, A. Fasolo, and S. De Marchis Hepatocyte Growth Factor Regulates Migration of Olfactory Interneuron Precursors in the Rostral Migratory Stream through Met-Grb2 Coupling J. Neurosci., June 4, 2008; 28(23): 5901 - 5909. [Abstract] [Full Text] [PDF]

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