Dataset Information

UTX Affects Neural Stem Cell Proliferation and Differentiation through PTEN Signaling.

ABSTRACT: Neural stem cell (NSC) proliferation and differentiation in the developing brain is a complex process precisely regulated by intrinsic and extrinsic signals. Although epigenetic modification has been reportedly involved in the regulation of the cerebral cortex, whether UTX, an H3K27me3 demethylase, regulates the development of cerebral cortex during the embryonic period is unclear. In this study, we demonstrate that Utx deficiency by knockdown and conditional knockout increases NSC proliferation and decreases terminal mitosis and neuronal differentiation. Furthermore, we find that impairment of cortical development caused by lack of Utx is less significant in males than in females. In addition, UTX demethylates H3K27me3 at the Pten promoter and promotes Pten expression. P-AKT and P-mTOR levels are increased in the Utx conditional knockout cortices. Finally, Utx or Pten overexpression can rescue the impairment of brain development caused by Utx loss. These findings may provide important clues toward deciphering brain diseases.

SUBMITTER: Lei X

PROVIDER: S-EPMC5998300 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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UTX Affects Neural Stem Cell Proliferation and Differentiation through PTEN Signaling.

Lei Xuepei X Jiao Jianwei J

Stem cell reports 20180315 4

Neural stem cell (NSC) proliferation and differentiation in the developing brain is a complex process precisely regulated by intrinsic and extrinsic signals. Although epigenetic modification has been reportedly involved in the regulation of the cerebral cortex, whether UTX, an H3K27me3 demethylase, regulates the development of cerebral cortex during the embryonic period is unclear. In this study, we demonstrate that Utx deficiency by knockdown and conditional knockout increases NSC proliferation ...[more]

PMID: 29551674

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Project description:: Phosphatase and tension homolog (PTEN) is a widely known negative regulator of insulin/phosphatidylinositol 3-kinase (PI3K) signaling. The PI3K/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) and Ras-extracellular signal-regulated kinase (Ras-ERK) signaling pathways are the chief mechanisms controlling the survival, proliferation, and differentiation of neural stem cells (NSCs). However, the roles of PTEN in Akt/mTOR and ERK signaling during proliferation and neuronal differentiation of human NSCs (hNSCs) are poorly understood. Treatment of proliferating hNSCs with a specific inhibitor of PTEN or overexpression of the PTEN inactive mutant G129E resulted in an increase in the expression levels of Ki67, p-S6 kinase (p-S6K), and p-ERK without affecting p-Akt expression during proliferation of hNSCs. Therefore, we focused on the regulatory effect of PTEN in S6K and ERK signaling during dopaminergic neuronal differentiation of hNSCs. Overexpression of PTEN during neuronal differentiation of hNSCs caused an increase in p-S6K expression and a decrease in p-ERK expression. Conversely, inhibition of PTEN increased p-ERK expression and decreased p-S6K expression. Inhibition of ERK by a specific chemical inhibitor, U0126, promoted neuronal generation, especially of tyrosine hydroxylase-positive neurons. p-S6K expression increased in a time-dependent manner during differentiation, and this effect was enhanced by U0126. These results indicated that PTEN promoted neuronal differentiation by inhibition of ERK signaling, which in turn induced activation of S6K. Our data suggest that ERK pathways participate in crosstalk with S6K through PTEN signaling during neuronal differentiation of hNSCs. These results represent a novel pathway by which PTEN may modulate the interplay between ERK and S6K signaling, leading to increased neuronal differentiation in hNSCs.SignificanceThis article adds to the body of knowledge about the mechanism of extracellular signal-regulated kinase (ERK)-mediated differentiation by describing the molecular function of phosphatase and tension homolog (PTEN) during the neuronal differentiation of human neural stem cells (hNSCs). Previous studies showed that S6K signaling promoted neuronal differentiation in hNSCs via the phosphatidylinositol 3-kinase Akt-mammalian target of rapamycin signaling pathway. A further series of studies investigated whether this S6 kinase-induced differentiation in hNSCs involves regulation of ERK signaling by PTEN. The current study identified a novel mechanism by which PTEN regulates neuronal differentiation in hNSCs, suggesting that activating PTEN function promotes dopaminergic neuronal differentiation and providing an important resource for future studies of PTEN function.

Dataset Information

UTX Affects Neural Stem Cell Proliferation and Differentiation through PTEN Signaling.

Publications

UTX Affects Neural Stem Cell Proliferation and Differentiation through PTEN Signaling.

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