GnRH neuronal migration and olfactory bulb neurite outgrowth are dependent on FGF receptor 1 signaling, specifically via the PI3K p110α isoform in chick embryo.

[kallmann syndrome]

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 (PI 3 K ) isoform-specific inhibitors , we demonstrate a central role for the PI 3 K p 110 α isoform as a downstream effector of FGFR 1 signaling for both GnRH neuronal migration and OB development . We show that signaling via the PI 3 K p 110 α 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 LY 294002 , a global PI 3 K inhibitor as well as an inhibitor to the PI 3 K p 110 α isoform into the olfactory placode of E 3 chick embryo impairs GnRH neuronal migration toward the forebrain . In contrast , in ovo PI 3 K inhibitor treatment produced no obvious defects on primary olfactory sensory neuron axonal targeting and bundle formation . We also demonstrate that anosmin-1 and FGF 2 induced neuronal migration of immortalized human embryonic GnRH neuroblast cells (FNC-B 4 -hTERT ) is mediated by modulating FGFR 1 signaling via the PI 3 K p 110 α isoform , specifically through phosphorylation of the PI 3 K downstream effectors , Akt and glycogen synthase kinase-3 β . Finally , we show that neurite outgrowth and elongation of OB neurons in E 10 chick OB explants are also dependent on the PI 3 K p 110 α isoform downstream of FGFR 1 . This study provides mechanistic insight into the etiology of Kallmann syndrome .