Modulation of the membrane-binding projection domain of tau protein: splicing regulation of exon 3

Abstract

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.