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Volume 17, Number 17, Issue of September 1, 1997 pp. 6657-6668
Copyright ©1997 Society for Neuroscience

Evidence That the Homeodomain Protein Gtx Is Involved in the Regulation of Oligodendrocyte Myelination

Received May 5, 1997; revised June 16, 1997; accepted June 20, 1997.

Raj Awatramani^{1, 6, 7}, Steven Scherer², Judith Grinspan³, Ellen Collarini⁴, Robert Skoff⁵, David O'Hagan⁶, James Garbern^{6, 7}, and John Kamholz^{6, 7}

¹ Graduate Group in Molecular Biology and ² Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, ³ Division of Neurology Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, ⁴ Department of Biology, University College, London WC1E 6BT, England, and ⁵ Department of Anatomy and Cell Biology, ⁶ Center for Molecular Medicine and Genetics, and ⁷ Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201

We have investigated the patterns of postnatal brain expression and DNA binding of Gtx, a homeodomain transcription factor. Gtx mRNA accumulates in parallel with the RNAs encoding the major structural proteins of myelin, myelin basic protein (MBP), and proteolipid protein (PLP) during postnatal brain development; Gtx mRNA decreases in parallel with MBP and PLP mRNAs in the brains of myelin-deficient rats, which have a point mutation in the PLP gene. Gtx mRNA is expressed in differentiated, postmitotic oligodendrocytes but is not found in oligodendrocyte precursors or astrocytes. These data thus demonstrate that Gtx is expressed uniquely in differentiated oligodendrocytes in postnatal rodent brain and that its expression is regulated in parallel with the major myelin protein mRNAs, encoding MBP and PLP, under a variety of physiologically relevant circumstances.

Using a Gtx fusion protein produced in bacteria, we have confirmed that Gtx is a sequence-specific DNA-binding protein, which binds DNA sequences containing a core AT-rich homeodomain binding site. Immunoprecipitation of labeled DNA fragments encoding either the MBP or PLP promoter regions with this fusion protein has identified several Gtx-binding fragments, and we have confirmed these data using an electrophoretic mobility shift assay. In this way we have identified four Gtx binding sites within the first 750 bp of the MBP promoter and four Gtx binding sites within the first 1.3 kb of the PLP promoter. In addition, inspection of the PLP promoter sequence demonstrates the presence of six additional Gtx binding sites. These data, taken together, strongly suggest that Gtx is important for the function of differentiated oligodendrocytes and may be involved in the regulation of myelin-specific gene expression.

Key words: brain development; DNA binding; Gtx; myelination; oligodendrocytes; gene expression

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