title: Novel mechanism for gonadotropin-releasing hormone neuronal migration involving Gas6/Ark signaling to p38 mitogen-activated protein kinase.
abstract: Gonadotropin-releasing hormone (GnRH) is the central regulator of the reproductive axis. Normal sexual maturation depends on the migration of GnRH neurons from the olfactory placode to the hypothalamus during development. Previously, we showed restricted expression of the membrane receptor adhesion-related kinase (Ark) in immortalized cell lines derived from migratory but not postmigratory GnRH neurons. In addition, Ark and GnRH transcripts were detected along the GnRH neuron migratory route in the E13 mouse cribriform plate. In the present study, we examined the role of Ark and its ligand, Gas6 (encoded by growth arrest-specific gene 6), in GnRH neuron migration. Gas6 stimulated lamellipodial extension, membrane ruffling, and chemotaxis of immortalized NLT GnRH neuronal cells via the Ark receptor. Gas6/Ark signaling promoted activation of the Rho family GTPase Rac, and adenoviral-mediated expression of dominant negative N17Rac abolished Gas6/Ark-induced actin cytoskeletal reorganization and migration of GnRH neuronal cells. In addition, p38 MAPK was activated downstream of Ark and Rac, and inhibition of p38 MAPK with either SB203580 or adenoviral dominant negative p38alpha also blocked Gas6/Ark-mediated migration. Finally, downstream of Rac and p38 mitogen-activated protein kinase (MAPK), Gas6/Ark signaling promoted activation of MAPK-activated protein kinase 2 and induced phosphorylation of HSP25, a known regulator of cortical actin remodeling. The data are the first to demonstrate a migratory signaling pathway downstream of Ark/Axl family receptors and suggest a previously unidentified role for p38 MAPK in neuronal migration. Furthermore, these studies support a potential role for Ark in the regulation of GnRH neuronal migration.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Research Service, Veterans Affairs Medical Center, Denver, Colorado 80220, USA.
authors.forename: Melissa P
authors.initials: MP
authors.lastname: Allen
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Linseman
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Udo
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.forename: Jerome B
authors.initials: JB
authors.lastname: Schaack
authors.forename: Brian
authors.initials: B
authors.lastname: Varnum
authors.forename: Eric R
authors.initials: ER
authors.lastname: Kandel
authors.forename: Kim A
authors.initials: KA
authors.lastname: Heidenreich
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Wierman
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology*; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D015513:Oncogene Proteins; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins / Q000502:physiology; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D007987:Gonadotropin-Releasing Hormone; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C057725:HSPB1 protein, human; C486113:Hsbp1 protein, mouse