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Neuropilins and their ligands are important in the migration of gonadotropin-releasing hormone neurons.

ABSTRACT: 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 fluorescence-activated 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.

SUBMITTER: Cariboni A

PROVIDER: S-EPMC6673474 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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Neuropilins and their ligands are important in the migration of gonadotropin-releasing hormone neurons.

Cariboni Anna A Hickok Jason J Rakic Sonja S Andrews William W Maggi Roberto R Tischkau Shelley S Parnavelas John G JG

The Journal of neuroscience : the official journal of the Society for Neuroscience 20070201 9

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 defascicul ...[more]

PMID: 17329436

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Project description:Gonadotropin-releasing hormone (GnRH) neurons originate outside the central nervous system (CNS) in the nasal placode where their migration to the basal forebrain is dependent on the integration of multiple signaling cues during development. The proper migration and establishment of the GnRH neuronal population within the CNS are critical for normal pubertal onset and reproductive function. The endopeptidase EP24.15 is expressed along the migratory path of GnRH neurons and cleaves the full-length GnRH to generate the metabolite GnRH-(1-5). Using the GN11 cell model, which is considered a pre-migratory GnRH neuronal cell line, we demonstrated that GnRH-(1-5) inhibits cellular migration in a wound closure assay by binding the orphan G protein-coupled receptor 173 (GPR173). In our current experiments, we sought to utilize an in vitro migration assay that better reflects the external environment that migrating GnRH neurons are exposed to during development. Therefore, we used a transwell assay where the inserts were coated with or without a matrigel, a gelatinous mixture containing extracellular matrix (ECM) proteins, to mimic the extracellular environment. Interestingly, GnRH-(1-5) inhibited the ability of GN11 cells to migrate only through ECM mimetic and was dependent on GPR173. Furthermore, we found that GN11 cells secrete TGF-?1, 2, and 3 but only TGF-?1 release and signaling were inhibited by GnRH-(1-5). To identify potential mechanisms involved in the proteolytic activation of TGF-?, we measured a panel of genes implicated in ECM remodeling. We found that GnRH-(1-5) consistently increased tissue inhibitors of metalloproteinase 1 expression, which is an inhibitor of proteinase activity, leading to a decrease in bioactive TGF-? and subsequent signaling. These results suggest that GnRH-(1-5) activating GPR173 may modulate the response of migrating GnRH neurons to external cues present in the ECM environment via an autocrine-dependent mechanism involving TGF-?.

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Neuropilins and their ligands are important in the migration of gonadotropin-releasing hormone neurons.

Publications

Neuropilins and their ligands are important in the migration of gonadotropin-releasing hormone neurons.

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