Background: Iron is essential for proper brain development in the fetal and early neonatal period. Iron represents a micronutrient for cellular metabolism and aerobic respiration, but cellular iron overload produces toxic build-up in many organs (including brain) via free radical formation. In thalassaemic patients with pubertal failure, iron overload is the most important factor afflicting the hypothalamic-pituitary axis, leading to hypogonadotrophic hypogonadism and growth failure. Methods: Mouse GN-11 cells (immature GnRH neurons with migratory ability) were used. Hepcidin, ferritin and transferrin receptor gene expression was evaluated by PCR. GN-11 chemotaxis was assessed by Boyden chamber assay. Activation of chemomigration-related cell signaling (extracellular signal-regulated kinase (ERK), 5' adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC)) was evaluated by Western blot analysis. Results: GN-11 cells express hepcidin, ferritin and transferrin receptor genes. 150 μM ferric ammoniumcitrate (FAC) treatment inhibited (-35%, P < 0.05) FBS-induced chemo-migration of GN-11 cells, which was rescued by pre-treatment with 100 μM deferoxamine, a specific iron chelator. Time-course experiments showed that 150 μM FAC was able to phosphorylate both ERK and AMPK after 10 min treatment. Specific ERK and AMPK inhibitors, U0126 and Compound C, respectively, abolished FAC-mediated signaling. Moreover, U0126 and Compound C (both 10 μM) counteracted FAC-driven phosphorylation of ACC, an AMPK downstream protein. Conclusions: The present data show that iron negatively affects neuron migration via ERK and AMPK. Among the consequences of this event, iron overload may impair migration of GnRH neurons from the olfactory placode into forebrain and hypothalamus, where they promote reproductive competence.
Could Iron Overload Impair the Migratory Ability of Neurons? Evidence from a Cell-Based Model / L. Steffani, M. Ruscica, F. Di Nitto, S. Fargion, P. Dongiovanni, L. Valenti, P. Magni. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - 181:Suppl. 1(2012 Sep), pp. S27-S27. ((Intervento presentato al convegno Joint Meeting of Pathology and Laboratory Diagnostics tenutosi a Udine nel 2012.
|Titolo:||Could Iron Overload Impair the Migratory Ability of Neurons? Evidence from a Cell-Based Model|
|Settore Scientifico Disciplinare:||Settore MED/05 - Patologia Clinica|
Settore MED/04 - Patologia Generale
Settore MED/09 - Medicina Interna
|Data di pubblicazione:||set-2012|
|Appare nelle tipologie:||01 - Articolo su periodico|