Author : Marcio De Paula
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (911 download)
Book Synopsis IGF-1 in Central and Peripheral Myelination by : Marcio De Paula
Download or read book IGF-1 in Central and Peripheral Myelination written by Marcio De Paula and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The myelin sheath around most axons constitutes the most abundant membrane structure in the vertebrate nervous system. In addition to its function in accelerating electrical conduction along axons, the myelin sheath generated by oligodendrocytes (OLGs) and Schwann cells have recently been shown to possess novel functions. Glial cells can provide nutritional support to associated axons and disruption of this interaction is involved in an array of different neurological diseases, including multiple sclerosis in the central nervous system and neuropathies in the peripheral nervous system. Insulin like-growth factor-1 (IGF-1) is one of the multiple signals that endow myelinating glia with trophic support during their proliferation and maturation, and ultimately axonal myelination. One way of regulating intracellular growth factor stimulation is provided by the phosphatase PTEN. PTEN is a key negative regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt transduction pathway, which is driven by growth factors such as IGF-1 and the type III neuregulin 1 (NRG1). We therefore hypothesized that a short-lived PTEN inhibition would enhance proliferation and differentiation of oligodendrocyte progenitors (OLPs) as well central and peripheral myelination induced by small amounts of IGF-1 and/or NRG1. We temporarily inhibited PTEN activity by treating rat and human OLPs cultured alone or with dorsal root ganglion neurons (DRGNs) with bisperoxovanadium compound (phen) or knocking down PTEN with siRNA. We found that phen potentiates IGF-1 actions by increasing proliferation of OLPs in a concentration-dependent manner, and caused a sustained and time-dependent activation of the main pathways: PI3K/Akt/mammalian target of rapamycin (mTOR) and MEK/ERK. Further, phen potentiated IGF-1 actions on the activation of the initiation and elongation stages of translation in OLPs. Most significantly, at low concentrations, IGF-1 and phen combined stimulated the differentiation of rat and human OLPs by increasing expression of cell-stage specific markers of differentiated OLGs. Notably, the treatment increased colocalization of the activated molecule S6rp with the myelin protein MBP, suggesting a prolonged induction of mTOR pathway during OLG differentiation. Concordantly, the PTEN inhibitor together with IGF-1 robustly augmented MBP accumulation in rat and human OLGs co-cultured with DRGNs in a longer timeframe by promoting the elaboration of organized myelinated fibers. In the peripheral nervous system, phen at different concentrations distinctly affected Schwann cell proliferation and myelination under IGF-1 and/or NRG1 treatment. Lower concentrations of phen together with IGF-1 and/or NRG1 enhanced myelination by increasing the number of myelin segments and Schwann cells expressing the transcription factor Krox-20 and p27kip1, two markers of Schwann cell differentiation/myelination. Additionally, higher induction of S6rp was detected in MBP+ myelin segments. Conversely, phen at higher concentration dramatically blocked the expression of peripheral myelin markers, which was partly recovered when combined with IGF-1 and/or NRG1. High amount of the PTEN inhibitor also amplified IGF-1 and/or NRG1 actions on the proliferation of Schwann cells cultured with DRGNs. Overall, our findings strongly suggest that central and peripheral myelination can be modulated by transiently inhibiting PTEN in the presence of the neurotrophic factors IGF-1 and/or NRG1." --
