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

Abstract

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 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.

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“…Fifty coding region mutations and 10 intronic mutations flanking E10 are shown. phorylation decreasing over time (Tuerde et al 2018). However, isoform switching and phosphorylation are regulated differently.…”

Tau filaments in neurodegenerative diseases

“…However, the presence of only one hyperphosphorylated 3R Tau isoform lacking Nterminal repeats is common to developing vertebrates. In mice the switch from 3R to 4R Tau occurs between postnatal days 9 and 18, with Tau phosphorylation also decreasing over that time [20]. However, isoform switching and phosphorylation are regulated differently.…”

Tau Filaments and the Development of Positron Emission Tomography Tracers

“…However, what is conserved is the expression of one hyperphosphorylated 3R Tau isoform lacking N-terminal repeats during vertebrate development. In mice the switch from 3R to 4R Tau occurs between postnatal days 9 and 18, with Tau phosphorylation also decreasing during that time ( 23 ). However, isoform switching and phosphorylation are regulated differently.…”