Myelin transcription factor 1 function in oligodendrocyte development

Abstract

Myelin transcription factor 1 (Myt1) is a CCHC zinc‐finger protein that is expressed in oligodendrocyte progenitors (OP) and is down‐regulated as oligodendrocytes differentiate and accumulate proteolipid protein (PLP). Myt1 contains six zinc‐finger DNA‐binding domains, a putative acidic transcriptional activation domain, and an alpha‐helical protein–protein interaction domain. Myt1 has two zinc‐fingers near the N‐terminus and four zinc‐fingers (4F) near the C‐terminus. Each set of zinc‐fingers can bind to the PLP promoter. The objective of this study was to determine the function of Myt1 by expressing the 4F domain of Myt1, which lacks the putative transcriptional activation domain and protein–protein interaction domain. We predicted the 4F domain would compete for Myt1 response elements, and lacking other functional domains would interfere with endogenous Myt1 function. A retroviral expression system that included a FLAG epitope tag was used to ectopically express the 4F domain of Myt1 in cultured rat neonatal OPs. OPs and their progeny exhibited nuclear immunoreactivity for the 4F‐FLAG fusion protein. Expression of 4F in OPs grown with PDGF and FGF mitogens reduced proliferation as compared to controls. In the absence of mitogens, expression of 4F inhibited the differentiation of OPs as assessed by morphological criteria, O1 immunostaining, and PLP mRNA expression. This 4F inhibition of OP differentiation along the oligodendrocyte pathway was not due to alternative differentiation along an astrocytic pathway. These data suggest that Myt1 regulates a critical transition in oligodendrocyte lineage development in modulating the OP proliferative response relative to terminal differentiation and myelin gene expression.Acknowledgements: Supported by USUHS grant RO70IE.