Ptp Alpha Is Required For Laminin-2-Induced Fyn-Akt Signaling To Drive Oligodendrocyte Differentiation

Extrinsic signals that regulate oligodendrocyte maturation and subsequent myelination are essential for central nervous system development and regeneration. Deficiency in the extracellular factor laminin-2 (Lm2, comprising the alpha 2 beta 1 gamma 1 chains), as occurs in congenital muscular dystrophy, can lead to impaired oligodendroglial development and aberrant myelination, but many aspects of Lm2-regulated oligodendroglial signaling and differentiation remain undefined. We show that receptor-like protein tyrosine phosphatase alpha (PTP alpha, also known as PTPRA) is essential for myelin basic protein expression and cell spreading during Lm2-induced oligodendrocyte differentiation. PTP alpha complexes with the Lm2 receptors alpha 6 beta 1 integrin and dystroglycan to transduce Fyn activation upon Lm2 engagement. In this way, PTP alpha mediates a subset of Lm2-induced signals required for differentiation, includeing mTOR-dependent Akt activation but not Erk1/2 activation. We identify N-myc downstream regulated gene-1 (NDRG1) as a PTP alpha-regulated molecule during oligodendrocyte differentiation, and distinguish Lm2 receptor-specific modes of Fyn-Akt-dependent and -independent NDRG1 phosphorylation. Altogether, this reveals an Lm2-regulated PTP alpha-Fyn-Akt signaling axis that is critical for key aspects of the gene expression and morphological changes that mark oligodendrocyte maturation.