Regulation of tau RNA maturation by thyroid hormone is mediated by the neural RNA-binding protein musashi-1.
The tau gene encodes a microtubule-associated protein expressed by neuronal and glial cells. Abnormal deposits of Tau protein are characteristic of several neurodegenerative disorders. Additionally, mutations affecting tau pre-mRNA alternative splicing of exon 10 are associated with frontotemporal dementia and Parkinsonism linked to chromosome 17. In rodents, this process is developmentally regulated by thyroid hormone (T3) causing the predominance of exon 10-containing transcripts. Here we demonstrate that musashi-1 (msi-1) gene is induced by T3 during rat brain development and in N2a cells. T3 increases msi-1 mRNA level in an actinomycin D-sensitive, cycloheximide-resistant fashion without affecting its half-life, which suggests a transcriptional effect. Both ectopic Msi-1 expression and T3 treatment increased the proportion of exon 10-containing tau transcripts. Furthermore, antisense msi-1 expression inhibited T3 action. Our results show that msi-1 mediates the posttranscriptional regulation of tau expression by T3.
Cuadrado
Ana
A
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Spain.
García-Fernández
Luis F
LF
Imai
Takao
T
Okano
Hideyuki
H
Muñoz
Alberto
A
D000818:Animals; D000831:Animals, Newborn; D016375:Antisense Elements (Genetics); D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014284:Triiodothyronine / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*
D016375:Antisense Elements (Genetics); D004268:DNA-Binding Proteins; C491296:Msi1 protein, rat; C104786:Msi1h protein, mouse; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D037042:Thyroid Hormone Receptors beta; D016875:tau Proteins; D014284:Triiodothyronine