期刊
MOLECULAR NEUROBIOLOGY
卷 56, 期 5, 页码 3380-3392出版社
SPRINGER
DOI: 10.1007/s12035-018-1310-7
关键词
Oligodendrocyte progenitor cell; Metalloproteinase; -Catenin; Akt; PKB; Tetraspanin; Astrocyte; Wnt7a
资金
- National Institutes of Health [5R21NS087578-02]
- National Multiple Sclerosis Society [RG5001-A-3]
The extracellular protein tissue inhibitor of metalloproteinase (TIMP)-1 is both a matrix metalloproteinase (MMP) inhibitor and a trophic factor. Mice lacking TIMP-1 exhibit delayed central nervous system myelination during postnatal development and impaired remyelination following immune-mediated injury in adulthood. We have previously determined that the trophic action of TIMP-1 on oligodendrocyte progenitor cells (OPCs) to mature into oligodendrocytes is independent of its MMP inhibitory function. However, the mechanism by which TIMP-1 promotes OPC differentiation is not known. To address this gap in our understanding, herein, we report that TIMP-1 signals via a CD63/1-integrin receptor complex to activate Akt (protein kinase B) to promote -catenin signaling in OPCs. The regulation of -catenin by TIMP-1 to promote OPC differentiation was counteracted, but not abrogated, by canonical signaling evoked by Wnt7a. These data provide a previously uncharacterized trophic action of TIMP-1 to regulate oligodendrocyte maturation via a CD63/1-integrin/Akt pathway mechanism. These findings contribute to our emerging understanding on the role of TIMP-1 as a growth factor expressed to promote CNS myelination during development and induced in the adult to promote myelin repair.
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