Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75NTR receptor-mediated activation of RhoA signaling pathways

PALANDRI A; ROZÉS SALVADOR V; ROZÉS SALVADOR, V.1; WOJNACKI, J. 1; HEREDIA, F.1 ; PALANDRI, A. 1; SHEIKH, KAZIN A.3; CACERES, A1; LOPEZ, P.H.H.1,2; VVIVNETTO A; SCHNNAAR R; LOPEZ PABLO H. H.

cell death & disease

nature publishing group

Año: 2015 p. 1 - 12

Myelin-associated glycoprotein (MAG) is a minor constituent of nervous system myelin, selectively expressed on the periaxonalmyelin wrap. By engaging multiple axonal receptors, including Nogo-receptors (NgRs), MAG exerts a nurturing and protectiveeffect the axons it ensheaths. Pharmacological activation of NgRs has a modulatory role on p75NTR-dependent postnatal apoptosisof motoneurons (MNs). However, it is not clear whether this reflects a physiological role of NgRs in MN development. NgRs are partof a multimeric receptor complex, which includes p75NTR, Lingo-1 and gangliosides. Upon ligand binding, this multimeric complexactivates RhoA/ROCK signaling in a p75NTR-dependent manner. The aim of this study was to analyze a possible modulatory role ofMAG on MN apoptosis during postnatal development. A time course study showed that Mag-null mice suffer a loss of MNs duringthe first postnatal week. Also, these mice exhibited increased susceptibility in an animal model of p75NTR-dependent MN apoptosisinduced by nerve-crush injury, which was prevented by treatment with a soluble form of MAG (MAG-Fc). The protective role of MAGwas confirmed in in vitro models of p75NTR-dependent MN apoptosis using the MN1 cell line and primary cultures. Lentiviralexpression of shRNA sequences targeting NgRs on these cells abolished protection by MAG-Fc. Analysis of RhoA activity using aFRET-based RhoA biosensor showed that MAG-Fc activates RhoA. Pharmacological inhibition of p75NTR/RhoA/ROCK pathway, oroverexpression of a p75NTR mutant unable to activate RhoA, completely blocked MAG-Fc protection against apoptosis. The role ofRhoA/ROCK signaling was further confirmed in the nerve-crush model, where pretreatment with ROCK inhibitor Y-27632 blockedthe pro-survival effect of MAG-Fc. These findings identify a new protective role of MAG as a modulator of apoptosis of MNs duringpostnatal development by a mechanism involving the p75NTR/RhoA/ROCK signaling pathway. Also, our results highlight therelevance of the nurture/protective effects of myelin on neurons.