ATAT1 regulates forebrain development and stress-induced tubulin hyperacetylation
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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.
KeywordsLateral ventricle Ventricular dilation Septum Striatum Stress signaling
This work was supported by research grants from Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and the Canadian Cancer Society (to X.-J.Y.). L.L. received stipend support from the China Scholarship Council, the Clifford C.F. Wong Fellowship program, a CIHR/FRSQ training grant in cancer research for the McGill Integrated Cancer Research Training Program and the Canderel Foundation.
LL carried out all experiments and wrote the manuscript; SJ and AW supervised the rotarod tests; MM helped perform some experiments with MEFs; LML and SM assisted with open field tests; XJY supervised the project and finalized the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest with the contents of this study.
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