PIKE is essential for oligodendroglia development and CNS myelination

Oligodendrocyte (OL) differentiation and myelin development are complex events regulated by numerous signal transduction factors. Here, we report that phosphoinositide-3 kinase enhancer L (PIKE-L) is required for OL development and myelination. PIKE-L expression is up-regulated when oligodendrocyte progenitor cells commit to differentiation. Conversely, depleting phosphoinositide-3 kinase enhancer (PIKE) expression by shRNA prevents oligodendrocyte progenitor cell differentiation. In both conventional PIKE knockout (PIKE^−/−) and OL-specific PIKE knockout mice, the number of OLs is reduced in the corpus callosum. PIKE^−/− OLs also display defects when forming myelin sheath on neuronal axons during neonatal development, which is partially rescued when PTEN is ablated. In addition, Akt/mTOR signaling is impaired in OL-enriched tissues of the PIKE^−/− mutant, leading to reduced expression of critical proteins for myelin development and hypomyelination. Moreover, myelin repair of lysolecithin-induced lesions is delayed in PIKE^−/− brain. Thus, PIKE plays pivotal roles to advance OL development and myelinogenesis through Akt/mTOR activation.Efficient propagation of action potentials depends on the presence of myelin sheath that spirals around the axon. As a membrane extension from oligodendrocytes (OLs), the myelin sheath has a unique lipid-rich composition that allows electrical insulation for high-speed conduction and fidelity of signal transfer (1). Generation of OLs is a developmentally regulated process, which involves the proliferation of oligodendrocyte progenitor cells (OPCs) at the germinal subventricular zones (SVZ), migration throughout the CNS, differentiation into mature OLs, and adhesion to the axon to form myelin (2). Although most OPCs first appear in early neonatal brain, maturation and myelination of OLs in rodents occur largely in postnatal life between P10 and P60 (1). The timing of s differentiation and myelin formation requires highly localized signaling mechanisms, which involves the coordinated activation/inactivation of Wnt/β-catenin, Hedgehog/Gli1, Jagged1/Notch, and PI3K/Akt/mTOR cascades (3). Disruption of these pathways via gene manipulation or modulation of their regulators results in defective OL development. For example, PI3K depletion causes reduced myelin expression in the cerebral cortex and striatum (4). On the other hand, mutation of PTEN, the negative regulator of PI3K/Akt cascade, causes thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum (CC) (5).Phosphoinositide 3-kinase enhancer L (PIKE-L) is a CNS-specific GTPase that belongs to the centaurin family (6, 7). It participates in numerous cellular events to regulate neuronal activity and survival. Our previous studies show that PIKE-L interacts with both netrin receptor (UNC5H) and metabotropic glutamate receptor I (mGlu₁) to prevent apoptotic cell death (8, 9). In addition, PIKE-L controls cell-surface trafficking of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid receptor and the formation of long-term potentiation in the postsynaptic neurons (10). Moreover, PIKE controls the neuronal dendritogenesis and survival through maintaining the integrity of the PI3K/Akt pathway (11). Indeed, PIKE is an important molecular switch to control the cellular PI3K/Akt activation as it links extracellular stimuli including netrin, glutamate, and neurotrophins to the intrinsic PI3K/Akt activities (12–14). Nevertheless, the functions of PIKE-L in nonneuronal cells such as OLs and astrocytes still remain unexplored. In this paper, we report that PIKE-L signals through the PI3K/Akt pathway to advance CNS myelinogenesis.