title: Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt.
abstract: We identified Ark, the mouse homolog of the receptor tyrosine kinase Axl (Ufo, Tyro7), in a screen for novel factors involved in GnRH neuronal migration by using differential-display PCR on cell lines derived at two windows during GnRH neuronal development. Ark is expressed in Gn10 GnRH cells, developed from a tumor in the olfactory area when GnRH neurons are migrating, but not in GT1-7 cells, derived from a tumor in the forebrain when GnRH neurons are postmigratory. Since Ark (Ax1) signaling protects from programmed cell death in fibroblasts, we hypothesized that it may play an antiapoptotic role in GnRH neurons. Gn10 (Ark positive) GnRH cells were more resistant to serum withdrawal-induced apoptosis than GT1-7 (Ark negative) cells, and this effect was augmented with the addition of Gas6, the Ark (Ax1) ligand. Gas6/Ark stimulated the extracellular signal-regulated kinase, ERK, and the serine-threonine kinase, Akt, a downstream component of the phosphoinositide 3-kinase (PI3-K) pathway. To determine whether ERK or Akt activation is required for the antiapoptotic effects of Gas6/Ark in GnRH neurons, cells were serum starved in the absence or presence of Gas6, with or without inhibitors of ERK and PI3-K signaling cascades. Gas6 rescued Gn10 cells from apoptosis, and this effect was blocked by coincubation of the cells with the mitogen-activated protein/ERK kinase (MEK) inhibitor, PD98059, or wortmannin (but not rapamycin). These data support an important role for Gas6/Ark signaling via the ERK and PI3-K (via Akt) pathways in the protection of GnRH neurons from programmed cell death across neuronal migration.
authors.affiliation: Veterans Affairs Medical Center and Department of Medicine, University of Colorado School of Medicine, Denver 80220, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Allen
authors.forename: C
authors.initials: C
authors.lastname: Zeng
authors.forename: K
authors.initials: K
authors.lastname: Schneider
authors.forename: X
authors.initials: X
authors.lastname: Xiong
authors.forename: M K
authors.initials: MK
authors.lastname: Meintzer
authors.forename: P
authors.initials: P
authors.lastname: Bellosta
authors.forename: C
authors.initials: C
authors.lastname: Basilico
authors.forename: B
authors.initials: B
authors.lastname: Varnum
authors.forename: K A
authors.initials: KA
authors.lastname: Heidenreich
authors.forename: M E
authors.initials: ME
authors.lastname: Wierman
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015152:Blotting, Northern; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000737:chemistry; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000502:physiology*; D015513:Oncogene Proteins; D011233:Precipitin Tests; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D000077191:Wortmannin; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6