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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Palandri, A. Salvador, V. R. Wojnacki, J. Vivinetto, A. L. Schnaar, R. L. Lopez, P. H. H. |
| Description | Country affiliation: Argentina Author Affiliation: Palandri A ( Laboratorio de Neurobiología, Instituto de Investigación Médica Mercedes y Martin Ferreyra, INIMEC-CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina.); Salvador VR ( Laboratorio de Neurobiología, Instituto de Investigación Médica Mercedes y Martin Ferreyra, INIMEC-CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina.); Wojnacki J ( Laboratorio de Neurobiología, Instituto de Investigación Médica Mercedes y Martin Ferreyra, INIMEC-CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina.); Vivinetto AL ( Laboratorio de Neurobiología, Instituto de Investigación Médica Mercedes y Martin Ferreyra, INIMEC-CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina.); Schnaar RL ( Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.); Lopez PH ( Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.) |
| Abstract | Myelin-associated glycoprotein (MAG) is a minor constituent of nervous system myelin, selectively expressed on the periaxonal myelin wrap. By engaging multiple axonal receptors, including Nogo-receptors (NgRs), MAG exerts a nurturing and protective effect the axons it ensheaths. Pharmacological activation of NgRs has a modulatory role on p75(NTR)-dependent postnatal apoptosis of motoneurons (MNs). However, it is not clear whether this reflects a physiological role of NgRs in MN development. NgRs are part of a multimeric receptor complex, which includes p75(NTR), Lingo-1 and gangliosides. Upon ligand binding, this multimeric complex activates RhoA/ROCK signaling in a p75(NTR)-dependent manner. The aim of this study was to analyze a possible modulatory role of MAG on MN 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 p75(NTR)-dependent MN apoptosis induced by nerve-crush injury, which was prevented by treatment with a soluble form of MAG (MAG-Fc). The protective role of MAG was confirmed in in vitro models of p75(NTR)-dependent MN apoptosis using the MN1 cell line and primary cultures. Lentiviral expression of shRNA sequences targeting NgRs on these cells abolished protection by MAG-Fc. Analysis of RhoA activity using a FRET-based RhoA biosensor showed that MAG-Fc activates RhoA. Pharmacological inhibition of p75(NTR)/RhoA/ROCK pathway, or overexpression of a p75(NTR) mutant unable to activate RhoA, completely blocked MAG-Fc protection against apoptosis. The role of RhoA/ROCK signaling was further confirmed in the nerve-crush model, where pretreatment with ROCK inhibitor Y-27632 blocked the pro-survival effect of MAG-Fc. These findings identify a new protective role of MAG as a modulator of apoptosis of MNs during postnatal development by a mechanism involving the p75(NTR)/RhoA/ROCK signaling pathway. Also, our results highlight the relevance of the nurture/protective effects of myelin on neurons. |
| File Format | HTM / HTML |
| e-ISSN | 20414889 |
| DOI | 10.1038/cddis.2015.228 |
| Journal | Cell Death and Disease |
| Volume Number | 6 |
| Language | English |
| Publisher | Nature Publishing Group |
| Publisher Date | 2015-09-03 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Signal Transduction Rhoa Gtp-binding Protein Receptors, Cell Surface Metabolism Discipline Cell Biology Animals Motor Neurons Myelin Proteins Gpi-linked Proteins Myelin-associated Glycoprotein Genetics Mice Apoptosis |
| Content Type | Text |
| Resource Type | Article |
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