Abstract
Oligodendrocytes (OLs) myelinate axons and provide electrical insulation and trophic support for neurons in the central nervous system (CNS). Platelet-derived growth factor (PDGF) is critical for steady-state number and differentiation of oligodendrocyte precursor cells (OPCs), but its downstream targets are unclear. Here, we show for the first time that Gab1, an adaptor protein of receptor tyrosine kinase, is specifically expressed in OL lineage cells and is an essential effector of PDGF signaling in OPCs in mice. Gab1 is downregulated by PDGF stimulation and upregulated during OPC differentiation. Conditional deletions of Gab1 in OLs cause CNS hypomyelination by affecting OPC differentiation. Moreover, Gab1 binds to downstream GSK3β and regulated its activity, and thereby affects the nuclear accumulation of β-catenin and the expression of a number of transcription factors critical to myelination. Our work uncovers a novel downstream target of PDGF signaling, which is essential to OPC differentiation and CNS myelination.
Highlights
In the central nervous system (CNS), oligodendrocytes (OLs) myelinate axons and provide electrical insulation and trophic support for neurons (Simons and Nave, 2015)
Gab1 was highly expressed in astrocytes and oligodendrocyte linage cells, whereas Gab2 was highly expressed in neurons, astrocytes and microglia (Figure 1A); ii) Gab1 was absent from cortical neurons (Figure 1A); and iii) Gab1 expression was remarkably elevated in mature OLs compared with oligodendrocyte precursor cells (OPCs) (Figure 1A), accompanying by the increased expression of myelin-specific proteins, myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) (Figure 1A and B)
Our results demonstrated that Platelet-derived growth factor (PDGF)-AA was sufficient to reverse the Gab1 expression augmented by triiodothyronine (Figure 1D)
Summary
In the central nervous system (CNS), oligodendrocytes (OLs) myelinate axons and provide electrical insulation and trophic support for neurons (Simons and Nave, 2015). The inactivation of PDGFa receptor (PDGFRa), which is majorly expressed in OPCs (Pringle et al, 1992), results in a reduced number of OPCs and precocious OPC differentiation (Zhu et al, 2014), whereas the activation of PDGFRa facilitates OPC division and migration (Frost et al, 2009; Tripathi et al, 2017) These studies demonstrate that PDGF serves as a gate controller of OPC development, it is surprising that the downstream targets of PDGF/PDGFRa signaling participating in OPC proliferation and differentiation are poorly understood
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