Negr1 is a member of IgLON adhesion protein family but its functions are largely unknown. In our previous work ((Pischedda et al. 2014), APPENDIX I) we identified Negr1 as a developmentally regulated synaptic protein. Thus we examined the consequences of Negr1 acute down regulation. Strikingly, we found that Negr1 ablation impairs neuronal maturation in vitro. In this project we demonstrated thanks to complementary biochemical and imaging approaches that Negr1 organizes trans-synaptic heterodimer and influences neurites outgrowth via MAPK signaling. In detail, we demonstrated that ectopic Negr1 is sufficient to improve neurite arborization and to rescue the morphological phenotype observed in Negr1 silenced cells. This function is dependent on the activation of MAPK pathway through tyrosine kinase receptors. In fact, we found that Negr1 physically and functionally interacts with FGFR2, modulates FGFR2 response to FGF and consequently influences MAPK pathway. FGFR2 pathway plays an important role during brain development. Not surprisingly, our investigation of the radial migration of newly generated cortical neurons revealed that Negr1- FGFR2 cross-talk controls cortical organization in vivo. Noteworthy, mutations in NEGR1 and FGFR2 genes have been recently identified as ASD candidates. Autism spectrum disorder (ASD) affects 0.9% of children and it is recognized as the most genetic of all developmental neuropsychiatric syndromes. Connectivity dysfunctions have been suggested as causative alterations in ASD. Given the functional, physical and genetic correlation among Negr1 and FGFR2 and the impact of Negr1 on neuron morphology and migration, Negr1-FGFR2 molecular cross talk might arise as a key mechanism during CNS development.
|Titolo:||THE IGLON FAMILY MEMBER NEGR1 PROMOTES NEURONAL ARBORIZATION AND MIGRATION VIA FGFR2|
|Data di pubblicazione:||18-feb-2016|
|Parole Chiave:||Negr1; adhesion; FGFR2; migration; ASD|
|Settore Scientifico Disciplinare:||Settore BIO/09 - Fisiologia|
|Citazione:||THE IGLON FAMILY MEMBER NEGR1 PROMOTES NEURONAL ARBORIZATION AND MIGRATION VIA FGFR2 ; tutor: G.Pietrini ; co-tutor: G.Piccoli. - Milano : Università degli studi di Milano. DIPARTIMENTO DI BIOTECNOLOGIE MEDICHE E MEDICINA TRASLAZIONALE, 2016 Feb 18. ((28. ciclo, Anno Accademico 2015.|
|Digital Object Identifier (DOI):||10.13130/pischedda-francesca_phd2016-02-18|
|Appare nelle tipologie:||Tesi di dottorato|