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Loss of PRMT5 promotes PDGFRa degradation during oligodendrocyte differentiation and myelination

Calabretta, Sara and Vogel, Gillian and Yu, Zhenbao and Choquet, Karine and Darbelli, Lama and Nicholson, Thomas and Kleinman, Claudia and Richard, Stephane (2018) Loss of PRMT5 promotes PDGFRa degradation during oligodendrocyte differentiation and myelination. Developmental cell, 46 (4). pp. 426-440. ISSN 15345807

Abstract

Platelet derived growth factor receptor α (PDGFRα) signaling is required for proliferation, commitment and maintenance of oligodendrocyte (OL) precursor cells (OPCs). PDGFRα signaling promotes OPC homeostasis and its attenuation signals OPC differentiation and maturation triggering the onset of myelination of the central nervous system (CNS). The initial steps of how PDGFRα signaling is attenuated are still poorly understood. Herein we show that decreased Protein Arginine MethylTransferase5 (PRMT5) expression, as occurs during OPC differentiation, is involved in the down-regulation of PDGFRα by modulating its cell surface bioavailability leading to its degradation in a Cbl-dependent manner. Mechanistically, loss of arginine methylation at R554 of the PDGFRα intracellular domain reveals a masked Cbl binding site at Y555. Physiologically, depletion of PRMT5 in OPCs results in severe CNS myelination defects. We propose that decreased PRMT5 activity initiates PDGFRα degradation to promote OL differentiation. More broadly, inhibition of PRMT5 may be used therapeutically to manipulate PDGFRα bioavailability.

Item Type: Article
Date Deposited: 01 Sep 2018 00:45
Last Modified: 01 Sep 2018 00:45
URI: https://oak.novartis.com/id/eprint/35397

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