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Stanislav Tomarev, Heung Sun Kwon, Naoki Nakaya, Mones Abu-Asab; Myocilin affects differentiation of oligodendrocytes and regulates myelination of the optic nerve via Lingo-1/RhoA signaling. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4002.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the functions of the glaucoma-associated protein, myocilin, in the optic nerve.
Optic nerve astrocytes and oligodendrocytes were isolated from postnatal day 6 (P6) or P7 mice. Optic nerves were examined by electron microscopy. Binding of myocilin to the Lingo-1/NgR1 complex was assessed by co-immunoprecipitation from the optic nerve and by binding assays using myocilin-alkaline phosphatase fusion proteins. Conductivity of the optic nerve was evaluated by a visual evoked potential test. Changes in gene expression were measured by RNA sequencing.
Myocilin was first detected in optic nerve astrocytes at P6 and its level increased with age. Myocilin was also detected in astrocytes but not oligodendrocytes that were isolated and cultured from the optic nerve. Addition of purified myocilin to immature oligodendrocytes stimulated their differentiation and increased mRNAs encoding myelin-associated proteins (MBP, MAG and MOG) when compared with untreated oligodendrocytes. MBP levels in the optic nerve of Myoc null mice were lower than in wild-type littermates at early postnatal stages (P5-P21). Electron microscopy examination of the optic nerve showed that myelin thickness was reduced and the microvilli at the nodes of Ranvier were disorganized in P13 Myoc null mice when compared with wild-type littermates. These defects in the myelination of the optic nerve were accompanied by a reduction of RhoA activity. Myocilin regulates RhoA activity through interaction with the Lingo-1/NgR1 complex. Changes in the myelination of the optic nerve led to a delayed latency and reduced amplitude of the visually evoked potential in adult Myoc null mice when compared to wild-type littermates. The levels of multiple mRNAs in the optic nerves of adult mice were different from wild-type, Myoc null and transgenic mice expressing mutated human myocilin (Tyr437His).
Our data suggest that myocilin regulates myelination of the optic nerve via the Lingo-1/RhoA signaling pathway.
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