Complete Sequence of 3′-Untranslated Region of Tau from Rat Central Nervous System: Implications for MRNA Heterogeneity

doi:10.1006/jmbi.1994.1508

Journal of Molecular Biology

Volume 241, Issue 2, 11 August 1994, Pages 325-331

https://doi.org/10.1006/jmbi.1994.1508 Get rights and content

Abstract

Tau is a family of microtubule associated proteins, heterogenous in molecular weights, which are expressed specifically in neurons. Tau is encoded by a single gene, while its transcript undergoes a complex and regulated alternative splicing, giving rise to several mRNA species that migrate on Northern blots at approximately 6 and 2 kb. In this report we characterize a full size transcript of tau mRNA from rat brain and demonstrate that it contains 5203 nucleotides (not including exon 2 and 3), which correlates well with the exact size of the transcript as analyzed by Northern blot using RNA standard size markers. The full length of the 3′-untranslated region contains 3848 bp and includes two polyadenylation signals which may yield the two size transcripts in the central nervous system. The first polyadenylation signal is located in the retained intron 13/14 and the second polyadenylation signal is 19 nucleotides before the poly(A) tail. Unspliced intron 13/14 was detected in all RNA preparations tested, including RNA from different ages and different regions of rat brain, RNA from dorsal root ganglia and from undifferentiated and differentiated PC12 cells. In none of the above tissues and cells was a spliced transcript lacking intron 13/14 detected.

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Citation Excerpt :
To analyze whether expression of G3BP1 or IMP1 also changes the ratio of HMW to LMW tau mRNA, we generated riboprobes for HMW or LMW tau mRNA, respectively (Fig. 7A). The calculated size for all tau mRNA isoforms is between ∼5.0 and 6.3 kb due to the long 3′UTR (∼3.8 kb (34)). Northern blotting revealed the presence of major bands at this size, thus confirming expression of full-length tau mRNA transcripts in the cells (Fig. 7B).
The neuronal microtubule-associated protein Tau is expressed in different variants, and changes in Tau isoform composition occur during development and disease. Here, we investigate a potential role of the multivalent tau mRNA-binding proteins G3BP1 and IMP1 in regulating neuronal tau expression. We demonstrate that G3BP1 and IMP1 expression induces the formation of structures, which qualify as neuronal ribonucleoprotein (RNP) granules and concentrate multivalent proteins and mRNA. We show that RNP granule formation leads to a >30-fold increase in the ratio of high molecular weight to low molecular weight tau mRNA and an ∼12-fold increase in high molecular weight to low molecular weight Tau protein. We report that RNP granule formation is associated with increased neurite formation and enhanced process growth. G3BP1 deletion constructs that do not induce granule formation are also deficient in inducing neuronal sprouting or changing the expression pattern of tau. The data indicate that granule formation driven by multivalent proteins modulates tau isoform expression and suggest a morphoregulatory function of RNP granules during health and disease.
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Tau is a microtubule-associated protein mainly expressed in neurons of central nervous system, which is crucial in the maintenance of these cells. It has a central role in the polymerization and stabilization of microtubules and in the traffic of organelles along axons and dendrites. Aggregates of hyperphosphorylated forms of tau protein participate in the formation of neurofibrillary tangles, which characterize numerous neurodegenerative disorders named tauopathies. The analysis of tau gene and the study of familial cases of tauopathies have led to the discovery of tau gene mutations that cause inherited dementia designated as Frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17). However, these familial cases remain rare compared to the sporadic tauopathies, the later involving both genetic and environmental etiologic factors. As tau pathology represents a primary pathogenic event in various neurodegenerative diseases, the hypothesis that tau genotype could influence the development of these diseases was tested by several groups. This review summarizes advances in the molecular genetics of the tau gene, as well as recent studies addressing the disease incidence of novel tau polymorphisms in different neurodegenerative diseases. Hopefully, the identification of several genetic defects of the tau gene will be helpful in improving our understanding of the role of tau protein in the pathogenesis of various neurodegenerative diseases.
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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.

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Journal of Molecular Biology

Sequence NoteComplete Sequence of 3′-Untranslated Region of Tau from Rat Central Nervous System: Implications for MRNA Heterogeneity

Abstract

Sequence Note
Complete Sequence of 3′-Untranslated Region of Tau from Rat Central Nervous System: Implications for MRNA Heterogeneity