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PMID:14614079

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Citation

Farhadi, HF, Lepage, P, Forghani, R, Friedman, HC, Orfali, W, Jasmin, L, Miller, W, Hudson, TJ and Peterson, AC (2003) A combinatorial network of evolutionarily conserved myelin basic protein regulatory sequences confers distinct glial-specific phenotypes. J. Neurosci. 23:10214-23

Abstract

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.

Links

PubMed

Keywords

Animals; Base Sequence; Cell Differentiation/physiology; Cells, Cultured; Cholera Toxin; Conserved Sequence; Demyelinating Diseases/chemically induced; Demyelinating Diseases/metabolism; Female; Gene Expression/physiology; Gene Targeting; Genes, Regulator/physiology; Genes, Reporter; Humans; Hypoxanthine Phosphoribosyltransferase/genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Myelin Basic Proteins/genetics; Neuroglia/metabolism; Oligodendroglia/metabolism; Phenotype; Plant Proteins; Ribosome Inactivating Proteins, Type 1; Sequence Homology, Nucleic Acid

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:MBP

GO:0019911: structural constituent of myelin sheath

ECO:0000315:

F

•Requires for normal myelin compaction (14614079). •Decrease the sciatic nerves of aged rats by increasing the number of myelin sheath lamellae. Fig.3

complete
CACAO 9531

MOUSE:MBP

acts_upstream_of_or_within

GO:0042552: myelination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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