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J Neurosci. 2005 Sep 21;25(38):8601-10.

Downregulation of platelet-derived growth factor-alpha receptor-mediated tyrosine kinase activity as a cellular mechanism for K+-channel regulation during oligodendrocyte development in situ.

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  • 1Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA. rchittajallu@cnmcresearch.org

Abstract

Oligodendrocyte maturation has been defined based on expression of developmentally regulated antigens. However, transitions at early stages of the lineage have not been functionally characterized fully in situ. Combining 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP)-promoter driven enhanced green fluorescent protein expression and whole-cell capacitance measurements permitted a reliable distinction between subcortical white matter NG2+ oligodendrocyte progenitors (OPs) and O4+ preoligodendrocytes (pre-OLs) in situ. We focused on K+ channels because their expression has been associated previously with the proliferation and differentiation potential of OPs. Using whole-cell patch clamp, we observed a downregulation of the delayed outward-rectifying current (IKDR) between the NG2+ and O4+ stages but no significant changes in transient K+-channel current (IKA) amplitude. Tyrosine kinase inhibition in NG2+ cells reduced IKDR amplitude with no effect on IKA, which mimicked the endogenous changes observed between OPs and pre-OLs. Tyrosine kinase inhibition also reduced the proliferative capacity of NG2+ OPs in slice cultures. Conversely, acute platelet-derived growth factor receptor-alpha (PDGFR-alpha) activation caused an increase of IKDR in NG2+ but not in O4+ cells. Consistent with this finding, PDGFR-alpha immunoreactivity was confined to NG2+ cells with undetectable levels in O4+ cells, suggesting that PDGFR-alpha signaling is absent in pre-OLs in situ. Importantly, the PDGF-induced increase of IKDR in NG2+ cells was prevented by tyrosine kinase inhibition. Together, these data indicate that PDGFR-alpha and tyrosine kinase activity act via a common pathway that influences functional expression of K+ channels and proliferative capacity of OPs in situ.

PMID:
16177027
[PubMed - indexed for MEDLINE]
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