Hepatocyte Growth Factor/Scatter Factor Facilitates Migration of GN-11 Immortalized LHRH Neurons

Giacobini, Paolo; Giampietro, Costanza; Fioretto, M.; Maggi, Roberto; Cariboni, Anna; Perroteau, Isabelle; Fasolo, Aldo

doi:10.1210/en.2002-220146

Cited by 51 publications

(58 citation statements)

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“…GN11 cells show a strong chemomigratory response in vitro (Maggi et al, 2000) and, as such, they have been used to investigate mechanisms involved in GnRH neuron migration (Giacobini et al, 2002;Cariboni et al, 2004Cariboni et al, , 2005. We first performed expression studies on GN11 cells to confirm our in vivo observations.…”

Section: Semaphorins and Neuropilins Are Involved In The Migration Ofmentioning

confidence: 85%

Neuropilins and Their Ligands Are Important in the Migration of Gonadotropin-Releasing Hormone Neurons

Cariboni¹,

Hickok²,

Rakić³

et al. 2007

J. Neurosci.

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Gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus play an important role in reproductive function. These cells originate in the nasal compartment and migrate into the basal forebrain in association with olfactory/vomeronasal nerves in embryonic life in rodents. Here, we studied the role of neuropilins and their ligands, semaphorins, in the development of the olfactory-GnRH system. We focused on Neuropilin-2 knock-out (Npn-2 ؊/؊ ) mice, because they are known to display defasciculation of olfactory nerves and reduced fertility. We found a significant decrease in the number of GnRH neurons in the hypothalamus and a marked reduction in their gonadal size. We then observed an abnormal increase of GnRH neurons in the noses of Npn-2 ؊/؊ mice, indicating that these cells failed to migrate into the forebrain. However, because neuropilins and semaphorins are involved in events of neuronal migration in the brain, we asked whether the observed reduction in GnRH neurons was directly attributable to the action of these molecules. Using fluorescenceactivated cell sorting and reverse transcription-PCR on mRNA derived from embryonic green fluorescent protein (GFP)-GnRH transgenic mice, we found expression of class 3 semaphorins and their receptors (neuropilin-1/2 and plexin-A1) in GnRH neurons. Furthermore, double-immunofluorescence experiments showed that migrating GnRH neurons, as well as associated olfactory fibers, express Npn-2 in the nasal region. We then used a line of immortalized GnRH neurons (GN11 cells) that display the same expression patterns for semaphorins and their receptors as GFP-GnRH cells and found that class 3 semaphorins and vascular endothelial growth factors modulate their migratory activity. These studies provide support for the direct involvement of neuropilins and their ligands in the establishment of the GnRH neuroendocrine system.

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Section: Semaphorins and Neuropilins Are Involved In The Migration Ofmentioning

confidence: 85%

Neuropilins and Their Ligands Are Important in the Migration of Gonadotropin-Releasing Hormone Neurons

Cariboni¹,

Hickok²,

Rakić³

et al. 2007

J. Neurosci.

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“…HGF is a target-derived chemotropic factor for different migratory systems, including cortical interneurons, striatal progenitors, and GnRH neurons (Powell et al, 2001;Giacobini et al, 2002Giacobini et al, , 2007Cacci et al, 2003). The OB plays an attracting role on RMS neuroblasts, and the glomerular and mitral cell layers seem to be relevant to this activity (Liu and Rao, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Converging evidence supports the notion that HGF acts as a chemoattractant for different neuronal cell types, such as motoneurons (Ebens et al, 1996), gonadotropin-releasing hormone (GnRH) cells (Giacobini et al, 2002), and striatal (Cacci et al, 2003) and cortical (Sun et al, 2002) progenitors. In addition, HGF is a motogen for interneuron precursors migrating from the ganglionic eminence to the cortex during embryonic brain development (Powell et al, 2001).…”

Section: Introductionmentioning

confidence: 85%

“…Hence, as an alternative approach for testing whether these portions of the SVZ-OB system are able to produce and release functional HGF, culture media conditioned by SVZ or aRMS tissue explants were collected and used for Met activation studies on GN11 immortalized GnRH neurons (Radovick et al, 1991). HGF stimulation on GN11 cells had previously been demonstrated to induce Met phosphorylation (Giacobini et al, 2002). In our experiments, GN11 cells in serum-free conditions were stimulated for 15 min with medium containing 10 or 50 ng/ml HGF (as positive controls) or with media conditioned by either SVZ or aRMS for 24 h and analyzed by Western blot using Met and P-Met antibodies.…”

Section: Hgf/met Signaling Is Activated In the Svz And Along The Rmsmentioning

confidence: 99%

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

Garzotto¹,

Giacobini²,

Crepaldi³

et al. 2008

Journal of Neuroscience

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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.

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“…The different origin may be indicative of some different maturational stages of the two cell lines, as demonstrated by the fact that GT1 cells retain many characteristics of the mature hypothalamic GnRH neurons (7)(8)(9)(10). On the contrary, it has been found recently (11,12) that GN cells retain the characteristics of immature GnRH neurons and show high migratory activity in vitro. However, the factors that regulate the outgrowth and targeting of olfactory axons from the nose to the hypothalamus during embryogenesis have not yet been identified in humans.…”

mentioning

confidence: 99%

Expression and Function of Gonadotropin-releasing Hormone (GnRH) Receptor in Human Olfactory GnRH-secreting Neurons

Romanelli

Barni

Maggi

et al. 2004

Journal of Biological Chemistry

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Olfactory neurons and gonadotropin-releasing hormone (GnRH) neurons share a common origin during organogenesis. Kallmann's syndrome, clinically characterized by anosmia and hypogonadotropic hypogonadism, is due to an abnormality in the migration of olfactory and GnRH neurons. We recently characterized the human FNC-B4 cell line, which retains properties present in vivo in both olfactory and GnRH neurons. In this study, we found that FNC-B4 neurons expressed GnRH receptor and responded to GnRH with time-and dose-dependent increases in GnRH gene expression and protein release (up to 5-fold). In addition, GnRH and its analogs stimulated cAMP production and calcium mobilization, although at different biological thresholds (nanomolar for cAMP and micromolar concentrations for calcium). We also observed that GnRH triggered axon growth, actin cytoskeleton remodeling, and a dosedependent increase in migration (up to 3-4-fold), whereas it down-regulated nestin expression. All these effects were blocked by a specific GnRH receptor antagonist, cetrorelix. We suggest that GnRH, secreted by olfactory neuroblasts, acts in an autocrine pattern to promote differentiation and migration of those cells that diverge from the olfactory sensory lineage and are committed to becoming GnRH neurons.

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Hepatocyte Growth Factor/Scatter Factor Facilitates Migration of GN-11 Immortalized LHRH Neurons

Cited by 51 publications

References 51 publications

Neuropilins and Their Ligands Are Important in the Migration of Gonadotropin-Releasing Hormone Neurons

Neuropilins and Their Ligands Are Important in the Migration of Gonadotropin-Releasing Hormone Neurons

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

Expression and Function of Gonadotropin-releasing Hormone (GnRH) Receptor in Human Olfactory GnRH-secreting Neurons

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