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Slit2 and Robo3 modulate the migration of GnRH-secreting neurons.

ABSTRACT: Gonadotropin-releasing hormone (GnRH) neurons are born in the nasal placode and migrate along olfactory and vomeronasal axons to reach the forebrain and settle in the hypothalamus, where they control reproduction. The molecular cues that guide their migration have not been fully identified, but are thought to control either cell movement directly or the patterning of their axonal substrates. Using genetically altered mouse models we show that the migration of GnRH neurons is directly modulated by Slit2 and Robo3, members of the axon guidance Slit ligand and Robo receptor families. Mice lacking Slit2 or Robo3 have a reduced number of GnRH neurons in the forebrain, but a normal complement of their supporting axons, pointing to a direct role for these molecules in GnRH neuron migration.

SUBMITTER: Cariboni A

PROVIDER: S-EPMC3424043 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Slit2 and Robo3 modulate the migration of GnRH-secreting neurons.

Cariboni Anna A Andrews William D WD Memi Fani F Ypsilanti Athena R AR Zelina Pavol P Chedotal Alain A Parnavelas John G JG

Development (Cambridge, England) 20120901 18

Gonadotropin-releasing hormone (GnRH) neurons are born in the nasal placode and migrate along olfactory and vomeronasal axons to reach the forebrain and settle in the hypothalamus, where they control reproduction. The molecular cues that guide their migration have not been fully identified, but are thought to control either cell movement directly or the patterning of their axonal substrates. Using genetically altered mouse models we show that the migration of GnRH neurons is directly modulated b ...[more]

PMID: 22912413

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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-?.

Dataset Information

Slit2 and Robo3 modulate the migration of GnRH-secreting neurons.

Publications

Slit2 and Robo3 modulate the migration of GnRH-secreting neurons.

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