Isoform-independent and -dependent phosphorylation of microtubule-associated protein tau in mouse brain during postnatal development

被引:35
作者
Tuerde, Dilina [1 ]
Kimura, Taeko [1 ]
Miyasaka, Tomohiro [2 ]
Furusawa, Kotaro [1 ]
Shimozawa, Aki [3 ]
Hasegawa, Masato [3 ]
Ando, Kanae [1 ]
Hisanaga, Shin-ichi [1 ]
机构
[1] Tokyo Metropolitan Univ, Dept Biol Sci, Hachioji, Tokyo 1920397, Japan
[2] Doshisha Univ, Fac Life & Med Sci, Neuropathol, Kyotanabe, Kyoto 6100394, Japan
[3] Tokyo Metropolitan Inst Med Sci, Setagaya Ku, Tokyo 1568506, Japan
关键词
alternative splicing; Alzheimer disease; brain; development; phosphorylation; Tau protein (Tau); AT8; Phos-tag; hypothyroidism; isoform; ALZHEIMERS-DISEASE; THYROID-HORMONE; FETAL-TAU; EXON; 10; EXPRESSION; CEREBELLUM; NEURODEGENERATION; PLASTICITY; DISORDERS; SEQUENCES;
D O I
10.1074/jbc.M117.798918
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Tau is a microtubule (MT)-associated protein that regulates MT dynamics in the axons of neurons. Tau binds to MTs via its C-terminal MT-binding repeats. There are two types of tau, those with three (3R) or four (4R) MT-binding repeats; 4R tau has a stronger MT-stabilizing activity than 3R tau. The MT-stabilizing activity of tau is regulated by phosphorylation. Interestingly, both the isoform and phosphorylation change at the time of neuronal circuit formation during postnatal development; highly phosphorylated 3R tau is replaced with 4R tau, which is less phosphorylated. However, it is not known how the transition of the isoforms and phosphorylation are regulated. Here, we addressed this question using developing mouse brains. Detailed analysis of developing brains revealed that the switch from 3R to 4R tau occurred during postnatal day 9 (P9) to P18 under the same time course as the conversion of phosphorylation from high to low. However, hypothyroidism, which is known to delay brain development, delayed the timing of tau dephosphorylation but not the exchange of isoforms, indicating that isoform switching and phosphorylation are not necessarily linked. Furthermore, we confirmed this finding by using mouse brains that expressed a single isoform of human tau. Human tau, either 3R or 4R, reduced phosphorylation levels during development even though the isoform did not change. We also found that 3R tau and 4R tau were phosphorylated differently in vivo even at the same developmental days. These results show for the first time that the phosphorylation and isoform alteration of tau are regulated differently during mouse development.
引用
收藏
页码:1781 / 1793
页数:13
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