Isoforms changes of tau protein during development in various species

doi:10.1016/S0165-3806(03)00056-7

Developmental Brain Research

Volume 142, Issue 2, 14 May 2003, Pages 121-127

https://doi.org/10.1016/S0165-3806(03)00056-7 Get rights and content

Abstract

Tau protein is one of the major microtubule-associated proteins of the vertebrate nervous system. Some kinds of isoforms, for example, six isoforms in humans, are generated from a single gene by alternative mRNA splicing. The expression of tau protein is widely believed to be developmentally and pathologically regulated. We examined developmental changes in tau protein from humans, rats, mice, and guinea pigs to determine the universal function of each isoform. Tau isoforms, composed of variants in the amino terminal and carboxyl terminal regions, gradually shifted through development in protein. The developmental changes in the carboxyl terminal region were found to be conserved in all species in which three-repeat tau isoforms were dominant in the fetus or neonate, while four-repeat tau isoforms were dominant in adult brain. On the other hand, the changes in the amino terminal region were not identical in these species. These observations were confirmed using isoform-specific antibodies which could discriminate the numbers of amino-terminus insertions and carboxy-terminus repeat insertions. Developmental regulation of 3- and 4-repeat tau isoforms may contribute to axonal development and neural plasticity.

Introduction

Tau protein is one of the major microtubule-associated proteins of the vertebrate nervous system. Six kinds of isoforms in humans are generated from a single gene by alternative mRNA splicing [9]. In addition to this multiple isoform expression, phosphorylation modifies the tau protein and may regulate its binding to microtubules. The tau protein contains three or four tandem repeats of 31 or 32 amino acids at the carboxyl terminus, and 29 or 58 amino acid inserts near the amino-terminus [9]. Thus, the full lengths of human cDNA clones have various sequences ranging from 352 to 441 amino acids in length.

In adult brain, differences among species are present in the expression of tau isoforms. There are three tau isoforms in adult rodents [3], [16], [23]. Each has four-repeat insert at the carboxyl terminus, while the adult human brain contains six tau isoforms, with three-repeat isoforms more abundant than four-repeat isoforms. The expression of tau protein is developmentally regulated. In fetal human brain, tau protein does not have amino terminal insertions and four-repeat isoforms, in contrast to adult human brain [7], [9], [19]. In fetal mouse brain [15], [16] and in fetal rat brain [3], [9], tau is thought to have no amino terminal inserts and three repeats inserts at the carboxyl terminus.

Tau is capable of promoting polymerization of tubulins [26] and preventing their dynamic instability by its binding to microtubules [5]. The four-repeat tau protein isoform promoted microtubule assembly at a faster rate than the three-repeat-containing isoform, though amino terminal insertions in tau protein did not contribute to microtubule assembly [7]. These effects of the transformation of tau protein may decrease the stability of microtubules, and may aid brain development, which requires a high degree of neural plasticity.

In this study, we examined the tau isoforms in various species to confirm the contribution of tau isoforms to formation of the developing brain.

Section snippets

Brain tissues

Human brain material was obtained from frozen tissues of an autopsy of a fetus (20 weeks of gestation) and of a control patient without neurological disease (70 years old). Postmortem delays were 1 and 12 h, respectively, and tissues were preserved at −80 °C until preparation. Brains of mice (ICR), rats (Wister) and guinea pigs were provided by SLC (Shizuoka, Japan). For rat and mouse, embryonic day 14 (E14), E17, postnatal day 0 (P0), P14, P28, and adult brains were used. For guinea pig, E52,

Characterization of each tau-specific antibody

The antibodies used in this study had been examined for specificity for recombinant tau-isoform proteins (Fig. 1B–F). Pool-2 antibody, AJ antibody, E2J antibody, and E3 antibody recognized all six isoforms, no amino-terminal insert and three and four repeats (0N3R and 0N4R), one amino-terminal insert and three and four repeats (1N3R and 1N4R), and two amino-terminal insert and three and four repeats (2N3R and 2N4R) in human tau species, respectively. R2 antibody was also found to recognized tau

Discussion

In this study, we demonstrated that the patterns of expression of tau isoforms differ among species and are regulated developmentally. Particularly we could study in detail at different stages with examining animal species that were not able to analyze in human. In early stages of development, only the tau isoform with three tandem repeats in the carboxy-terminal region was found in all four species examined, human, rat, mouse and guinea pig. During development, the repeat number of this domain

Acknowledgements

We thank Dr Kenneth S. Kosik (Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School) for his kind suggestion and generous gift of human tissues throughout this study. This study was supported in part by a grant-in-aid for Scientific Research on Priority Areas (C)-Advanced Brain Science Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to HM). This study was also supported by grants-in-aid from Uehara Memorial Foundation,

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Research reportIsoforms changes of tau protein during development in various species

Abstract

Introduction

Section snippets

Brain tissues

Characterization of each tau-specific antibody

Discussion

Acknowledgements

Brain Res.

Neuron

Neuron

Mol. Brain Res.

FEBS Lett.

Neuron

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Trends Neurosci.

The tau mutation (val337met) disrupts cytoskeletal networks of microtubules

Neuroreport

Tau is enriched on dynamic microtubules in the distal region of growing axons

J. Neurosci.

Developmental changes in tau phosphorylation: fetal tau is transiently phosphorylated in a manner similar to paired helical filament-tau characteristic of Alzheimer’s disease

J. Neurochem.

MAP-1B/TAU functional redundancy during laminin-enhanced axonal growth

J. Cell Sci.

Research report
Isoforms changes of tau protein during development in various species