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The Journal of Neuroscience, November 12, 2003, 23(32):10214-10223

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Development/Plasticity/Repair
A Combinatorial Network of Evolutionarily Conserved Myelin Basic Protein Regulatory Sequences Confers Distinct Glial-Specific Phenotypes

Hooman F. Farhadi,¹ Pierre Lepage,³ Reza Forghani,¹ Hana C. H. Friedman,¹ Wayel Orfali,² Luc Jasmin,⁴ Webb Miller,⁵ Thomas J. Hudson,³ and Alan C. Peterson¹

¹Royal Victoria Hospital and ²Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 1A1, Canada, ³McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 1A4, Canada, ⁴Department of Neurological Surgery, University of California, San Francisco, California 94143-0112, and ⁵Department of Statistics, Pennsylvania State University, University Park, Pennsylvania 16802

Myelin basic protein (MBP) is required for normal myelin compaction and is implicated in both experimental and human demyelinating diseases. In this study, as an initial step in defining the regulatory network controlling MBP transcription, we located and characterized the function of evolutionarily conserved regulatory sequences. Long-range human-mouse sequence comparison revealed over 1 kb of conserved noncoding MBP 5' flanking sequence distributed into four widely spaced modules ranging from 0.1 to 0.4 kb. We demonstrate first that a controlled strategy of transgenesis provides an effective means to assign and compare qualitative and quantitative in vivo regulatory programs. Using this strategy, single-copy reporter constructs, designed to evaluate the regulatory significance of modular and intermodular sequences, were introduced by homologous recombination into the mouse hprt (hypoxanthine-guanine phosphoribosyltransferase) locus. The proximal modules M1 and M2 confer comparatively low-level oligodendrocyte expression primarily limited to early postnatal development, whereas the upstream M3 confers high-level oligodendrocyte expression extending throughout maturity. Furthermore, constructs devoid of M3 fail to target expression to newly myelinating oligodendrocytes in the mature CNS. Mutation of putative Nkx6.2/Gtx sites within M3, although not eliminating oligodendrocyte targeting, significantly decreases transgene expression levels. High-level and continuous expression is conferred to myelinating or remyelinating Schwann cells by M4. In addition, when isolated from surrounding MBP sequences, M3 confers transient expression to Schwann cells elaborating myelin. These observations define the in vivo regulatory roles played by conserved noncoding MBP sequences and lead to a combinatorial model in which different regulatory modules are engaged during primary myelination, myelin maintenance, and remyelination.

Key words: myelin basic protein; transcription; HPRT transgenesis; oligodendrocyte; Schwann cell; remyelination

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Received July 31, 2003; revised September 9, 2003; accepted September 13, 2003.

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