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Cell Mol Life Sci. 2019 Sep;76(18):3621-3640. doi: 10.1007/s00018-019-03088-3. Epub 2019 Apr 5.

ATAT1 regulates forebrain development and stress-induced tubulin hyperacetylation.

Author information

1
The Rosalind and Morris Goodman Cancer Research Center, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada.
2
Department of Medicine, McGill University, Montreal, Canada.
3
Department of Biology, McGill University, Montreal, Canada.
4
Department of Obstetrics and Gynecology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
5
The Rosalind and Morris Goodman Cancer Research Center, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, Canada. xiang-jiao.yang@mcgill.ca.
6
Department of Medicine, McGill University, Montreal, Canada. xiang-jiao.yang@mcgill.ca.
7
Department of Biochemistry, McGill University, Montreal, Canada. xiang-jiao.yang@mcgill.ca.
8
McGill University Health Center, Montreal, QC, Canada. xiang-jiao.yang@mcgill.ca.

Abstract

α-Tubulin acetyltransferase 1 (ATAT1) catalyzes acetylation of α-tubulin at lysine 40 in various organisms ranging from Tetrahymena to humans. Despite the importance in mammals suggested by studies of cultured cells, the mouse Atat1 gene is non-essential for survival, raising an intriguing question about its real functions in vivo. To address this question, we systematically analyzed a mouse strain lacking the gene. The analyses revealed that starting at postnatal day 5, the mutant mice display enlarged lateral ventricles in the forebrain, resembling ventricular dilation in human patients with ventriculomegaly. In the mice, ventricular dilation is due to hypoplasia in the septum and striatum. Behavioral tests of the mice uncovered deficits in motor coordination. Birth-dating experiments revealed that neuronal migration to the mutant septum and striatum is impaired during brain development. In the mutant embryonic fibroblasts, we found mild defects in cell proliferation and primary cilium formation. Notably, in these cells, ATAT1 is indispensable for tubulin hyperacetylation in response to high salt, high glucose, and hydrogen peroxide-induced oxidative stress. We investigated the role of ATAT1 in the hematopoietic system using multicolor flow cytometry and found that this system remains normal in the mutant mice. Although tubulin acetylation was undetectable in a majority of mutant tissues, residual levels were detected in the heart, skeletal muscle, trachea, oviduct, thymus and spleen. This study thus not only establishes the importance of ATAT1 in regulating mouse forebrain development and governing tubulin hyperacetylation during stress responses, but also suggests the existence of an additional α-tubulin acetyltransferase.

KEYWORDS:

Lateral ventricle; Septum; Stress signaling; Striatum; Ventricular dilation

PMID:
30953095
DOI:
10.1007/s00018-019-03088-3
[Indexed for MEDLINE]

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