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V. Pernet, S. Joly, F. Christ, M. E. Schwab; Nogo-A Gene Disruption Alters Oligodendrocyte Maturation in the Optic Nerve. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4364. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Nogo-A was initially identified as a major myelin-derived inhibitor for axonal regeneration in the adult CNS. However, during postnatal development, Nogo-A is expressed by both neurons and oligodendrocytes (OLs). Here, we proposed that Nogo-A may participate to OL development in the visual system.
We analyzed OL development in transgenic mice deficient for Nogo-A (Nogo-A-/-) or MAG (MAG-/-). The pattern of expression for Nogo-A, myelin-associated glycoprotein (MAG), myelin-basic protein (MBP), proteolipid proteins (PLP/DM20) and 2',3'-cyclic nucleotide 3' phosphodiesterase (CNPase) was assessed by quantitative RT-PCR (qRT-PCR). The migration of oligodendrocyte precursor cells (OPCs) in the optic nerve was followed by using olig2 antibody, specific for OPCs/OLs, on longitudinal sections (10 µm) between P0 and P28. The differentiation of OLs was investigated by examining MBP, PLP and CNPase by immunohistochemistry, western blot analysis and qRT-PCR. Myelination was studied by electron microscopy (EM) in P15 and P28 optic nerves. The axoglial contact was observed in optic nerves by double immunostaining for paranodin and sodium channel (NaCh) at P15.
After P3, Nogo-A mRNA drastically increased in the WT optic nerve while it steadily dropped in the retina. The migration of Olig2-positive OPCs was similar in the optic nerve with or without Nogo-A or MAG. In Nogo-A-/- optic nerves, the immunostaining for MBP was weaker relative to WT mice, suggesting that OL differentiation is altered in mutants. Consistently, in Nogo-A-/-, MBP, PLP/DM20 and CNPase mRNAs were ~40% lower than in WT optic nerve at P10. In addition, the level of MBP protein was reduced in lysates of Nogo-A-/- cerebella compared with WT at P15. By EM, only ~30% axons were surrounded by a myelin sheath in Nogo-A-/- and MAG-/- optic nerves compared with ~70% in WT tissues. Axonal diameters were significantly smaller in Nogo-A-/- and MAG-/- than in WT control. However, by ~30 days, the density of myelinated axons, the MBP protein expression and axon sizes were no longer decreased in transgenic mice. Moreover, Nogo-A-/- axons showed a normal distribution of paranodin and NaCh, reflecting the proper axoglial connection.
Our results revealed that Nogo-A disruption affects OL maturation and further suggest that Nogo-A may influence relapsing events in demyelinating diseases such as multiple sclerosis.
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