Myelin-Associated Glycoprotein modulates programmed cell death of motoneurons during early postnatal development via NgR/p75NTR receptor-mediated activation of RhoA signaling pathway

PALANDRI, ANABELA; ROZÉS SALVADOR, VICTORIA; WOJNAKI, JOSE; VIVINETTO, ANA LAURA; RONALD L. SCHNAAR; PABLO HECTOR HORACIO LOPEZ

Congreso; Reunión Anual de la Sociedad Argenitna de Investigación en Neurociencias; 2014

Myelin-Associated Glycoprotein (MAG) is a minor constituent of the nervous system expressed at the periaxonal layer of myelinated axons. By Nogo-receptors (NgRs), MAG exerts a nurture effect on axons it ensheaths. Pharmacological activation of NgRs has a modulatory role on p75NTR-dependent postnatal apoptosis of motoneurons (MNs). NgRs are part of a receptor complex which includes p75NTR, Lingo-1 and gangliosides. Upon ligand binding, this multimeric complex activates RhoA/ROCK signalling in a p75NTR-dependent manner. The aim of this study was to analyze a modulatory role of MAG on MNs apoptosis during postnatal development. A time course study showed that Mag-null mice suffer a loss of MNs during the first postnatal week. Also these mice exhibited increased susceptibility in an animal model of MNs apoptosis induced by nerve-crush injury, which was prevented by MAG-Fc treatment. The protective role of MAG was confirmed in in vitro models of p75NTR-dependent MN apoptosis. Lentiviral expression of shRNA sequences targeting NgRs abolished protection by MAG-Fc. Analysis of RhoA activity using a FRET-based RhoA biosensor showed that MAG-Fc activates RhoA. Pharmacological inhibition of p75NTR/RhoA/ROCK pathway or overexpression of a p75NTR mutant lacking binding to RhoA blocked MAG-Fc protection. Overall these findings identify a new protective role of MAG as a modulator of apoptosis of MNs during postnatal development by a mechanism involving p75NTR/RhoA/ROCK signaling pathway.