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Posttranscriptional regulation of myelin protein gene expression
A T Campagnoni1, J M Verdi, A N Verity
1Mental Retardation Research Center, U.C.L.A. Center for the Health Sciences 90024.
Abstract:
Regulation of myelin protein gene expression occurs at many different levels including transcription, mRNA translocation, translation, and posttranslational modification of myelin proteins prior to their assembly into the membrane. Translocation of myelin basic protein (MBP) mRNAs into oligodendrocyte processes was observed in vivo and in primary cultures, but no such translocation was observed for the mRNAs encoding the proteolipid protein (PLP) or myelin-associated glycoprotein. More than 99% of the mRNAs encoding 2'3'-cyclic nucleotide phosphodiesterase (CNP) remained associated with cell bodies. In the jimpy mutant, MBP mRNA translocation appeared to be impaired, but translocation occurred normally in quaking brains in vivo. We have found that steroids, such as glucocorticoids, stimulate the translation of MBP and PLP mRNAs in cell-free systems and inhibit the translation of CNP mRNA. This pattern of regulation is consistent with compositional changes noted in myelin during development. We have localized a nine nucleotide segment within the 5'-untranslated region of the MBP mRNA that is involved in the action of steroids on translation of this mRNA. We have also determined that the protein synthetic step modulated by the steroids is chain initiation, enhancing the rate at which new ribosomal subunits bind to the MBP mRNAs.
Insights
Steroids regulate myelin protein synthesis by controlling mRNA translation, specifically enhancing myelin basic protein (MBP) and proteolipid protein (PLP) mRNA translation through chain initiation. This impacts myelin composition during development.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Myelin protein gene expression is regulated at multiple levels, including mRNA translocation and translation.
- Myelin basic protein (MBP) mRNA translocation occurs in oligodendrocyte processes, unlike proteolipid protein (PLP) and myelin-associated glycoprotein (MAG) mRNAs.
- The regulation of myelin protein synthesis is crucial for myelin structure and function during development.
Purpose of the Study:
- To investigate the role of steroids in regulating myelin protein gene expression.
- To identify the specific mechanisms by which steroids affect myelin mRNA translation.
- To determine the impact of steroid regulation on myelin composition.
Main Methods:
- Studied mRNA translocation in vivo and in primary oligodendrocyte cultures.
- Utilized cell-free systems to examine steroid effects on MBP, PLP, and CNP mRNA translation.
- Localized a specific nucleotide segment in MBP mRNA involved in steroid-mediated translation.
- Identified the protein synthesis step modulated by steroids as chain initiation.
Main Results:
- MBP mRNA translocation was impaired in the jimpy mutant but normal in quaking brains.
- Steroids, like glucocorticoids, stimulate MBP and PLP mRNA translation while inhibiting CNP mRNA translation in cell-free systems.
- A nine-nucleotide segment in the 5'-untranslated region of MBP mRNA mediates steroid action on translation.
- Steroids enhance the rate of ribosomal subunit binding to MBP mRNAs, modulating chain initiation.
Conclusions:
- Steroids play a significant role in regulating myelin protein synthesis at the translational level.
- The observed translational regulation by steroids is consistent with developmental changes in myelin composition.
- Targeting the 5'-untranslated region of MBP mRNA offers a mechanism for steroid-controlled myelin protein production.