title: GnRH neuronal migration and olfactory bulb neurite outgrowth are dependent on FGF receptor 1 signaling, specifically via the PI3K p110α isoform in chick embryo.
abstract: Fibroblast growth factor (FGF) signaling is essential for both olfactory bulb (OB) morphogenesis and the specification, migration, and maturation of the GnRH-secreting neurons. Disruption of FGF signaling contributes to Kallmann syndrome characterized by both anosmia and sexual immaturity. However, several unanswered questions remain as to which specific FGF receptor (FGFR)-1 signaling pathways are necessary for OB and GnRH neuronal development. Here, using pharmacological phosphatidylinositol 3-kinase (PI3K) isoform-specific inhibitors, we demonstrate a central role for the PI3K p110α isoform as a downstream effector of FGFR1 signaling for both GnRH neuronal migration and OB development. We show that signaling via the PI3K p110α isoform is required for GnRH neuronal migration in explant cultures of embryonic day (E) 4 chick olfactory placodes. We also show that in ovo administration of LY294002, a global PI3K inhibitor as well as an inhibitor to the PI3K p110α isoform into the olfactory placode of E3 chick embryo impairs GnRH neuronal migration toward the forebrain. In contrast, in ovo PI3K inhibitor treatment produced no obvious defects on primary olfactory sensory neuron axonal targeting and bundle formation. We also demonstrate that anosmin-1 and FGF2 induced neuronal migration of immortalized human embryonic GnRH neuroblast cells (FNC-B4-hTERT) is mediated by modulating FGFR1 signaling via the PI3K p110α isoform, specifically through phosphorylation of the PI3K downstream effectors, Akt and glycogen synthase kinase-3β. Finally, we show that neurite outgrowth and elongation of OB neurons in E10 chick OB explants are also dependent on the PI3K p110α isoform downstream of FGFR1. This study provides mechanistic insight into the etiology of Kallmann syndrome.
authors.affiliation: Centre for Neuroendocrinology, University College London Medical School, Royal Free Campus, London NW3 2PF, United Kingdom. youli.hu@ucl.ac.uk
authors.forename: Youli
authors.initials: Y
authors.lastname: Hu
authors.forename: Subathra
authors.initials: S
authors.lastname: Poopalasundaram
authors.forename: Anthony
authors.initials: A
authors.lastname: Graham
authors.forename: Pierre-Marc
authors.initials: PM
authors.lastname: Bouloux
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D002642:Chick Embryo; D002867:Chromones / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009830:Olfactory Bulb / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002867:Chromones; D007987:Gonadotropin-Releasing Hormone; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D051496:Receptor, Fibroblast Growth Factor, Type 1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one