Article

Tau isoforms which contain the domain encoded by exon 6 and their role in neurite elongation

Neurobiology of Developmental Disorders, Shriver Center for Mental Retardation, Waltham, Massachusetts 02452, USA.
Journal of Cellular Biochemistry (Impact Factor: 3.37). 04/2004; 91(5):880-95. DOI: 10.1002/jcb.20029
Source: PubMed

ABSTRACT The regulation of tau protein expression during different stages of cellular differentiation and development as well as its functional role in morphogenesis, neurofibrillary tangle formation, and neurodegeneration have been topics of extensive study but have not been completely clarified yet. Tau undergoes complex regulated splicing in the mammalian nervous system. Our previous study with tau exon 6 demonstrated that it shows a splicing regulation profile which is distinct from that of the other tau exons as well as a unique expression pattern which is spatially and temporally regulated. In this study, we investigated the expression, localization, and effects of tau isoforms which contain exon 6 in neuroblastoma cells which stably overexpress them. We found that expression of one particular combination of tau exons (the longest adult isoform plus the domain of exon 6) significantly inhibits neurite elongation.

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    • "The isoform 6c has a microtubule-binding domain that is missing in the 6p and 6d isoforms. It has been determined that the presence of exon 6c inhibits neurite extension in RA-differentiated SY5Y cells, whereas the presence of exon 6d does not (Luo et al., 2004). Interestingly, Leroy et al. (2006b) found that inclusion of exon 6c decreases in DM1 brains compared with control brains whereas inclusion of 6d increases, and that alternative splicing modulators CELF5 and CELF6 influence exon 6 splicing in COS cells. "
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    • "In support of this hypothesis, the 2 + 3 + 6 + 10 + isoform drastically decreases process length if over-expressed in SY5Y neuroblastoma cells (Luo et al. 2004a). This postulated role of exon 6 is consistent with its relative levels of expression in fetal versus adult brain (Wei and Andreadis 1998; Luo et al. 2004a; Leroy et al. 2006). "
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    ABSTRACT: Tau is a microtubule-associated protein whose transcript undergoes complex regulated splicing in the mammalian nervous system. Exon 6 of the gene is an alternatively spliced cassette whose expression profile differs from that of the other tau regulated exons, implying the involvement of distinct regulatory factors. Previous work had established the existence and use of two additional 3' splice sites within exon 6 and the influence of splicing factors polypyrimidine binding protein (PTB) and U2AF on its splicing. The present work shows that exon 6 isoforms exist in distinct ratios in different compartments of the nervous system and that splicing of exon 6 is governed by multiple branch points, exonic cis elements and additional trans factors. Recent results show that tau exon 6 is specifically suppressed in the brains of people who suffer from myotonic dystrophy type 1. The understanding of how tau exon 6 splicing is regulated may give us insights into the disease.
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    • "Recently, expression of Tau isoform including exons 2 and 3 plus exon 6 in neuroblastoma cells was shown to inhibit neurite outgrowth [12]. Exon 1 is part of the promoter, and is transcribed but not translated. "
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