Protein phosphatase 2ACα gene knock-out results in cortical atrophy through activating hippo cascade in neuronal progenitor cells

Liu, Bo; Sun, Li-Hua; Huang, Yan-Fei; Guo, Li-Jun; Luo, Li-Shu

doi:10.1016/j.biocel.2017.12.015

Cited by 29Hippo pathway signaling and YAP/TAZNeurogenesis and neuroplasticity mechanismsGenetics and Neurodevelopmental Disorders

Protein phosphatase 2ACα gene knock-out results in cortical atrophy through activating hippo cascade in neuronal progenitor cells

Liu, Bo, Sun, Li-Hua, Huang, Yan-Fei, Guo, Li-Jun, Luo, Li-Shu·2018·The International Journal of Biochemistry & Cell Biology

DOI 10.1016/j.biocel.2017.12.015

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Abstract

Protein phosphatase 2ACα (PP2ACα), a vital member of the protein phosphatase family, has been studied primarily as a regulator for the development, growth and protein synthesis of a lot of cell types. Dysfunction of PP2ACα protein results in neurodegenerative disease; however, this finding has not been directly confirmed in the mouse model with PP2ACα gene knock-out. Therefore, in this study presented here, we generated the PP2ACα gene knock-out mouse model by the Cre-loxP targeting gene system, with the purpose to directly observe the regulatory role of PP2ACα gene in the development of mouse's cerebral cortex. We observe that knocking-out PP2ACα gene in the central nervous system (CNS) results in cortical neuronal shrinkage, synaptic plasticity impairments, and learning/memory deficits. Further study reveals that PP2ACα gene knock-out initiates Hippo cascade in cortical neuroprogenitor cells (NPCs), which blocks YAP translocation into the nuclei of NPCs. Notably, p73, directly targeted by Hippo cascade, can bind to the promoter of glutaminase2 (GLS2) that plays a dominant role in the enzymatic regulation of glutamate/glutamine cycle. Finally, we find that PP2ACα gene knock-out inhibits the glutamine synthesis through up-regulating the activity of phosphorylated-p73 in cortical NPCs. Taken together, it concludes that PP2ACα critically supports cortical neuronal growth and cognitive function via regulating the signaling transduction of Hippo-p73 cascade. And PP2ACα indirectly modulates the glutamine synthesis of cortical NPCs through targeting p73 that plays a direct transcriptional regulatory role in the gene expression of GLS2.

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Additional research in neuronal progenitor cells identified upregulation of Hippo signaling, witnessed by increased phosphorylation of MST1/2 (Ser180/183), LATS1 (Ser909) and YAP (Ser127), and inhibited nuclear translocation of YAP.
“Additional research in neuronal progenitor cells (NPCs) identified an upregulation of Hippo signaling, witnessed by an increased phosphorylation of MST1/2 (Ser180/183), LATS1 (Ser909) and YAP (Ser127), and inhibited nuclear translocation of YAP.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [47]
p53-like protein p73 phosphorylation (Tyr99) was enhanced, which could additionally contribute to the observed increase in apoptotic signaling and diminished proliferation of the Cα-/- neuronal progenitor cells.
“Furthermore, p53-like protein p73 phosphorylation (Tyr99) was enhanced, which could additionally contribute to the observed increase in apoptotic signaling and diminished proliferation of the Cα -/-NPCs [47].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [47]
Conditional loss of Ppp2ca in the nervous system resulted in severe microcephaly and cortical atrophy at P7, characterized by loss of cortical neurons and decreased thickness of cortical layers II-V.
“Conditional loss of Ppp2ca in the nervous system resulted in severe microcephaly and cortical atrophy at P7, characterized by loss of cortical neurons and decreased thickness of cortical layers II-V [47].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [47]
The animals performed poorly in a Morris water maze test, indicating learning and memory defects.
“The animals performed poorly in a Morris water maze test, indicating learning and memory defects.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [47]

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Authors: Liu, B., Sun, L.-H., Huang, Y.-F., Guo, L.-J., & Luo, L.-S.
Affiliations: University of Maryland, Baltimore (US)
Shandong University (CN)
Jilin University (CN)
Corresponding author: Luo, Li-Shu
ORCID: Liu, Bo
Venue: The International Journal of Biochemistry & Cell Biology
Publisher: Elsevier BV
Published: 2018-02
Volume: 95
Pages: 53-62
ISSN: 1357-2725 (ISSN-L)
DOI: 10.1016/j.biocel.2017.12.015
OpenAlex: W2776124176
Cited by: 29
References: 42
Citations by year: 2026: 2 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 2
FWCI: 1.17
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: The International Journal of Biochemistry & Cell Biology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: protein phosphatase 2A, cortical atrophy, Hippo signaling pathway, YAP nuclear translocation, p73, GLS2, glutamine synthesis, glutamate-glutamine cycle, synaptic plasticity, learning and memory impairment, brain development
MeSH terms: Tumor Protein p73, Serine-Threonine Kinase 3, Hippo Kinases, Animals, Atrophy, Cells, Cultured, Crosses, Genetic, Embryo, Mammalian, Glutaminase, Hippocampus, Learning Disabilities, Memory Disorders, Mice, Transgenic, Nerve Tissue Proteins, Phosphorylation, Promoter Regions, Genetic, Protein Processing, Post-Translational, Signal Transduction, Protein Serine-Threonine Kinases, Genes, Reporter, Mice, Knockout, RNA Interference, Malformations of Cortical Development, Protein Phosphatase 2, Neural Stem Cells

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Protein phosphatase 2ACα gene knock-out results in cortical atrophy through activating hippo cascade in neuronal progenitor cells

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