TY - JOUR
T1 - Nuclear PTEN deficiency causes microcephaly with decreased neuronal soma size and increased seizure susceptibility
AU - Igarashi, Atsushi
AU - Itoh, Kie
AU - Yamada, Tatsuya
AU - Adachi, Yoshihiro
AU - Kato, Takashi
AU - Murata, Daisuke
AU - Sesaki, Hiromi
AU - Iijima, Miho
N1 - Funding Information:
This work was supported by National Institutes of Health Grants GM084015 (to M. I.) and GM123266 (to H. S.) and the Allegheny Health Network–Sidney Kimmel Comprehensive Cancer Center (to M. I. and H. S.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2018 Michalski and Williams Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2018/6/15
Y1 - 2018/6/15
N2 - Defects in phosphatase and tensin homolog (PTEN) are associated with neurological disorders and tumors. PTEN functions at two primary intracellular locations: The plasma membrane and the nucleus. At the membrane, PTEN functions as a phosphatidylinositol (3,4,5)-trisphosphate phosphatase and suppresses PI 3-kinase signaling that drives cell growth and tumorigenesis. However, the in vivo function of nuclear PTEN is unclear. Here, using CRISPR/Cas9, we generated a mouse model in which PTEN levels in the nucleus are decreased. Nuclear PTEN-deficient mice were born with microcephaly and maintained a small brain during adulthood. The size of neuronal soma was significantly smaller in the cerebellum, cerebral cortex, and hippocampus. Also, these mice were prone to seizure. No changes in PI 3-kinase signaling were observed. By contrast, the size of other organs was unaffected. Therefore, nuclear PTEN is essential for the health of the brain by promoting the growth of neuronal soma size during development.
AB - Defects in phosphatase and tensin homolog (PTEN) are associated with neurological disorders and tumors. PTEN functions at two primary intracellular locations: The plasma membrane and the nucleus. At the membrane, PTEN functions as a phosphatidylinositol (3,4,5)-trisphosphate phosphatase and suppresses PI 3-kinase signaling that drives cell growth and tumorigenesis. However, the in vivo function of nuclear PTEN is unclear. Here, using CRISPR/Cas9, we generated a mouse model in which PTEN levels in the nucleus are decreased. Nuclear PTEN-deficient mice were born with microcephaly and maintained a small brain during adulthood. The size of neuronal soma was significantly smaller in the cerebellum, cerebral cortex, and hippocampus. Also, these mice were prone to seizure. No changes in PI 3-kinase signaling were observed. By contrast, the size of other organs was unaffected. Therefore, nuclear PTEN is essential for the health of the brain by promoting the growth of neuronal soma size during development.
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U2 - 10.1074/jbc.RA118.002356
DO - 10.1074/jbc.RA118.002356
M3 - Article
C2 - 29735527
AN - SCOPUS:85049165512
SN - 0021-9258
VL - 293
SP - 9292
EP - 9300
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 24
ER -