Modulation of the membrane-binding projection domain of tau protein: splicing regulation of exon 3.
Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. The N-terminal domain of the protein interacts with the axonal membrane, and is modulated by differential inclusion of exons 2 and 3. These two tau exons are alternatively spliced cassettes, in which exon 3 never appears independently of exon 2. Previous work with tau minigene constructs indicated that exon 3 is intrinsically suboptimal and its primary regulator is a weak branch point. In this study, we confirm the role of the weak branch point in the regulation of exon 3 but also show that the exon is additionally regulated by a combination of exonic enhancers and silencers. Furthermore, we demonstrate that known splicing regulators affect the ratio of exon 3 isoforms, Lastly, we tentatively pinpoint the site of action of several splicing factors which regulate tau exon 3.
Arikan
Meltem Cevik
MC
Department of Biomedical Sciences, E.K. Shriver Center for Mental Retardation, Waltham, MA 02454, USA.
Memmott
John
J
Broderick
Jennifer A
JA
Lafyatis
Robert
R
Screaton
Gavin
G
Stamm
Stefan
S
Andreadis
Athena
A
D000818:Animals; D001369:Axons / Q000378:metabolism*; D001483:Base Sequence / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism*; D022081:Cell Surface Extensions / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005091:Exons / Q000235:genetics*; D020868:Gene Silencing / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009420:Nervous System / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
D020033:Protein Isoforms; D016875:tau Proteins