The tyrosine kinase Fyn plays a key role in oligodendrocyte differentiation and myelination in the central nervous system, but the molecules responsible for regulating Fyn activation in these processes remain poorly defined. Here we show that receptor-like protein-tyrosine phosphatase ␣ (PTP␣) is an important positive regulator of Fyn activation and signaling that is required for the differentiation of oligodendrocyte progenitor cells (OPCs). PTP␣ is expressed in OPCs and is up-regulated during differentiation. We used two model systems to investigate the role of PTP␣ in OPC differentiation: the rat CG4 cell line where PTP␣ expression was silenced by small interfering RNA, and oligosphere-derived primary OPCs isolated from wild-type and PTP␣-null mouse embryos. In both cell systems, the ablation of PTP␣ inhibited differentiation and morphological changes that accompany this process. Although Fyn was activated upon induction of differentiation, the level of activation was severely reduced in cells lacking PTP␣, as was the activation of Fyn effector molecules focal adhesion kinase, Rac1, and Cdc42, and inactivation of Rho. Interestingly, another downstream effector of Fyn, p190RhoGAP, which is responsible for Rho inactivation during differentiation, was not affected by PTP␣ ablation. In vivo studies revealed defective myelination in the PTP␣ ؊/؊ mouse brain. Together, our findings demonstrate that PTP␣ is a critical regulator of Fyn activation and of specific Fyn signaling events during differentiation, and is essential for promoting OPC differentiation and central nervous system myelination.Myelination is an essential feature of the vertebrate nervous system. The myelin sheath provides electrical insulation to axons and facilitates transmission of nerve impulses. Other important roles of myelin are to contribute to neuronal survival and development, as well as neurotransmission and synaptic activity (1). Deficiencies in myelination during development, or demyelination that can occur following injury or in diseases such as multiple sclerosis, lead to neurological disorders (2-4).The formation of the highly specialized multilamellar myelin sheath by oligodendrocytes (OLs) 3 in the CNS occurs early in development, following proliferation and migration of oligodendrocyte progenitor cells (OPCs) to their final axonal targets (5). The molecular mechanisms that regulate OPC differentiation and OL maturation and myelination remain poorly understood. Consistent with the physical juxtaposition of axons and enwrapping oligodendroglia, axonal signals have been identified that influence OPC differentiation and/or myelination, such the axonal ligands Jagged1 and contactin that engage the glial receptor Notch (6, 7). Other signals, such as those described below that are provided by components of the extracellular matrix or the presence or absence of growth factors, are also important in these processes.The Src family tyrosine kinase (SFK) Fyn is an essential participant and central coordinator of OL differentiation, maturatio...

Thiazolidinediones induce adipocyte differentiation and thereby limit proliferative potential; hence, early investigations focused on their ability to modulate cellular proliferation and apoptosis.