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

Abstract

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.

Developmental Regulation of Gonadotropin-releasing Hormone Gene Expression by the MSX and DLX Homeodomain Protein Families

“…Previous findings suggest that GnRH expression itself is involved in furthering the commitment and migratory state of the GnRH neurons (11). We therefore hypothesized that GnRH transcriptional activity would differ between the migratory and mature GnRH neuronal cell lines.…”

“…Expression of GnRH during prenatal development actively contributes to the identity and migratory ability of the septohypothalamic population. Indeed, GnRH itself, is involved in furthering the commitment and migratory state of the GnRH neuronal precursor in an ultrashort, positive feedback loop by upregulating expression of the GnRH gene, stimulating axon growth, cytoskeletal remodeling and increasing the migration of neuronal precursors (11). Thus, expression of GnRH during embryonic development likely promotes the characteristics of the maturing GnRH neuron that are essential for reproductive ability.…”

Human neurons express type I GnRH receptor and respond to GnRH I by increasing luteinizing hormone expression

“…6) has previously been reported for the human olfactory FNC-B4 cell line (Romanelli et al 2004), as well as numerous other cancer cell lines originating from the prostate, kidney, skin, lymphocytes, liver, larynx, pancreas, colon, and brain (Fekete et al 1989, Friess et al 1991, Pati & Habibi 1995, van Groeninghen et al 1998, Krebs et al 2002, Moretti et al 2002, Ben-Yehudah & Lorberboum-Galski 2004. Rat primary cortical neurons express the same GnRHR I variants as neuroblastoma cells (Fig.…”

The role of Dlx homeogenes in early development of the olfactory pathway

“…We then examined the expression of the Dlx5 lacZ reporter in various sub-populations of MgCs in E14.5 normal embryos, by performing double immunostaining for bgal (Dlx5) and either DCX (Gleeson et al 1999), GnRH (Romanelli et al 2004), or S100 (Astic et al 1998;Tennent and Chuah 1996) on frontal sections of Dlx5 +/lacZ embryos. As seen with Xgal staining, abundant bgal+ cells were found near the medial surface of the OB (Fig.…”