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Regulation of cell proliferation by nucleocytoplasmic dynamics of postnatal and embryonic exon-II-containing MBP
Abstract:
The only known structural protein required for formation of myelin, produced by oligodendrocytes in the central nervous system, is myelin basic protein (MBP). This peripheral membrane protein has different developmentally-regulated isoforms, generated by alternative splicing. The isoforms are targeted to distinct subcellular locations, which is governed by the presence or absence of exon-Il, although their functional expression is often less clear. Here, we investigated the role of exon-Il-containing MBP isoforms and their link with cell proliferation. Live-cell imaging and FRAP analysis revealed a dynamic nucleocytoplasmic translocation of the exon-II-containing postnatal 21.5-kDa MBP isoform upon mitogenic modulation. Its nuclear export was blocked upon treatment with leptomycin B, an inhibitor of nuclear protein export. Next to the postnatal MBP isoforms, embryonic exon-II-containing MBP (e-MBP) is expressed in primary (immature) oligodendrocytes. The e-MBP isoform is exclusively present in OLN-93 cells, a rat-derived oligodendrocyte progenitor cell line, and interestingly, also in several non-CNS cell lines. As seen for postnatal MBPs, a similar nucleocytoplasmic translocation upon mitogenic modulation was observed for e-MBP. Thus, upon serum deprivation, e-MBP was excluded from the nucleus, whereas re-addition of serum re-established its nuclear localization, with a concomitant increase in proliferation. Knockdown of MBP by shRNA confirmed a role for e-MBP in OLN-93 proliferation, whereas the absence of e-MBP similarly reduced the proliferative capacity of non-CNS cell lines. Thus, exon-Il-containing MBP isoforms may regulate cell proliferation via a mechanism that relies on their dynamic nuclear import and export, which is not restricted to the oligodendrocyte lineage.
Insights
Exon-II-containing myelin basic protein (MBP) isoforms dynamically translocate between the nucleus and cytoplasm, influencing cell proliferation. This mechanism is not limited to oligodendrocytes but also affects other cell types.
Area of Science:
- Cell Biology
- Neuroscience
- Molecular Biology
Background:
- Myelin basic protein (MBP) is crucial for myelin formation in the central nervous system, produced by oligodendrocytes.
- MBP exists in various isoforms generated by alternative splicing, with exon-II influencing subcellular localization and function.
- The precise role of exon-II-containing MBP isoforms in cell proliferation remains unclear.
Purpose of the Study:
- To investigate the function of exon-II-containing MBP isoforms, specifically their role in cell proliferation.
- To elucidate the mechanism of nucleocytoplasmic translocation of MBP isoforms in response to mitogenic signals.
Main Methods:
- Live-cell imaging and Fluorescence Recovery After Photobleaching (FRAP) to track MBP isoform dynamics.
- Treatment with leptomycin B to inhibit nuclear export.
- Mitogenic modulation using serum deprivation and re-addition.
- Oligonucleotide progenitor cell line (OLN-93) and non-CNS cell lines.
- MBP knockdown using short hairpin RNA (shRNA).
Main Results:
- Postnatal 21.5-kDa MBP isoform exhibited dynamic nucleocytoplasmic translocation upon mitogenic stimulation, with nuclear export inhibited by leptomycin B.
- Embryonic exon-II-containing MBP (e-MBP) showed similar translocation patterns in OLN-93 cells and non-CNS cell lines.
- Serum deprivation led to nuclear exclusion of e-MBP, while serum re-addition promoted nuclear localization and increased proliferation.
- MBP knockdown confirmed e-MBP's role in OLN-93 cell proliferation and reduced the proliferative capacity of non-CNS cell lines.
Conclusions:
- Exon-II-containing MBP isoforms regulate cell proliferation through dynamic nuclear import and export.
- This mechanism is not exclusive to oligodendrocytes and extends to other cell types.
- MBP's nucleocytoplasmic shuttling represents a novel pathway linking myelin protein dynamics to cell proliferation control.
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