Nuclear PTEN deficiency causes microcephaly with decreased neuronal soma size and increased seizure susceptibility

• Published in: The Journal of biological chemistry Vol. 293; no. 24; pp. 9292 - 9300
• Main Authors: Igarashi, Atsushi, Itoh, Kie, Yamada, Tatsuya, Adachi, Yoshihiro, Kato, Takashi, Murata, Daisuke, Sesaki, Hiromi, Iijima, Miho
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.06.2018; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Substitution; Animals; brain; Brain - metabolism; Brain - pathology; Cell Biology; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Nucleus - pathology; cell signaling; Cell Size; CRISPR-Cas Systems; Female; Gene Editing; genome editing; lipid signaling; Male; Mice; Microcephaly - complications; Microcephaly - genetics; Microcephaly - pathology; mouse; mouse genetics; Mutation; Neurons - metabolism; Neurons - pathology; nucleus; phosphatase and tensin homolog (PTEN); phosphatidylinositide 3-kinase (PI 3-kinase); Phosphatidylinositol 3-Kinases - metabolism; PIP3 signaling; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Seizures - complications; Seizures - genetics; Seizures - pathology; Signal Transduction; PIP3 signaling; mouse; genome editing; cell signaling; phosphatase and tensin homolog (PTEN); mouse genetics; nucleus; phosphatidylinositide 3-kinase (PI 3-kinase); brain; lipid signaling
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA118.002356

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.