A distal upstream enhancer from the myelin basic protein gene regulates expression in myelin-forming schwann cells.
In peripheral nerves, large caliber axons are ensheathed by myelin-elaborating Schwann cells. Multiple lines of evidence demonstrate that expression of the genes encoding myelin structural proteins occurs in Schwann cells in response to axonal instructions. To gain further insight into the mechanisms controlling myelin gene expression, we used reporter constructs in transgenic mice to search for the DNA elements that regulate the myelin basic protein (MBP) gene. Through this in vivo investigation, we provide evidence for the participation of multiple, widely distributed, positive and negative elements in the overall control of MBP expression. Notably, all constructs bearing a 0.6 kb far-upstream sequence, designated Schwann cell enhancer 1 (SCE1), expressed at high levels in myelin-forming Schwann cells. In addition, robust targeting activity conferred by SCE1 was shown to be independent of other MBP 5' flanking sequence. These observations suggest that SCE1 will make available a powerful tool to drive transgene expression in myelinating Schwann cells and that a focused analysis of the SCE1 sequence will lead to the identification of transcription factor binding sites that positively regulate MBP expression.
Forghani
R
R
Laboratory of Developmental Biology, Department of Neurology and Neurosurgery, Molecular Oncology Group H-5, McGill University, Montreal, Quebec, Canada, H3A 1A1.
Garofalo
L
L
Foran
D R
DR
Farhadi
H F
HF
Lepage
P
P
Hudson
T J
TJ
Tretjakoff
I
I
Valera
P
P
Peterson
A
A
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D051767:Early Growth Response Protein 2; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D004676:Myelin Basic Protein / Q000096:biosynthesis* / Q000235:genetics; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D010525:Peripheral Nerves / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D004676:Myelin Basic Protein; D012333:RNA, Messenger; D014157:Transcription Factors; D001616:beta-Galactosidase