title: Molecular basis of thyroid hormone regulation of myelin basic protein gene expression in rodent brain.
abstract: Regulation of myelin basic protein (MBP) gene expression by thyroid hormone has been investigated in rodent brain. Quantitation of the 4 major alternatively spliced transcripts by RNase protection assay showed that the individual mRNAs, corresponding to MBP isoforms 21.5, 18.5, 17, and 14 kDa, were decreased from 2- to 17-fold at all ages studied (4-60 days) in hypothyroid animals when compared to euthyroid, but the timing of onset of expression was not altered. MBP mRNA was also reduced in young adult rats thyroidectomized at the age of 5-6 weeks and was restored to normal by thyroxine administration. Nuclear run-off assays showed that the rate of MBP gene transcription is dependent on thyroid state. Co-transfection of MBP (-256/+1)-chloramphenicol acetyltransferase chimeric gene with a plasmid expressing thyroid hormone receptor alpha, and in the presence of 3,5,3'-triiodothyronine, into NIH3T3 or NG108-15, increased chloramphenicol acetyltransferase expression 4-fold. Using a footprinting technique and Spodoptera frugiperda 9 (Sf9) nuclear extract infected with baculovirus expressing TR alpha, we have identified a single DNA-binding site (-186/-163) for the receptor. A part of this region contains the AGGACA sequence found in thyroid hormone-responsive elements of other 3,5,3'-triiodothyronine-regulated genes. Our finding of a specific hormone-receptor interaction with the MBP promoter region is the first direct demonstration of a thyroid hormone-responsive element in a brain-specific gene.
authors.affiliation: Clinical Endocrinology Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: A
authors.initials: A
authors.lastname: Farsetti
authors.forename: T
authors.initials: T
authors.lastname: Mitsuhashi
authors.forename: B
authors.initials: B
authors.lastname: Desvergne
authors.forename: J
authors.initials: J
authors.lastname: Robbins
authors.forename: V M
authors.initials: VM
authors.lastname: Nikodem
mesh_terms: D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D005786:Gene Expression Regulation; D007037:Hypothyroidism / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D013963:Thyroid Hormones / Q000502:physiology*; D013974:Thyroxine / Q000502:physiology; D014158:Transcription, Genetic; D014284:Triiodothyronine / Q000502:physiology
chemical_list: D004676:Myelin Basic Protein; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014284:Triiodothyronine; D004247:DNA; D003850:Deoxyribonuclease I; D013974:Thyroxine