Pen-2 Negatively Regulates the Differentiation of Oligodendrocyte Precursor Cells into Astrocytes in the Central Nervous System
- Jinxing Hou1,*,
- Huiru Bi1,*,
- Zhuoyang Ye1,
- Wenhui Huang2,
- Gang Zou3,
- Xiaochuan Zou1,
- Yun Stone Shi1,
- Ying Shen4,
- Quanhong Ma5,
- Frank Kirchhoff2,
- Yimin Hu6, and
- Guiquan Chen1
- 1State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China
- 2Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Homburg, D-66421, Germany
- 3Department of General Surgery, Second Clinical Medical College, Shenzhen People's Hospital, Jinan University, Shenzhen, 518000, China
- 4Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- 5Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Second Affiliated Hospital, Soochow University, Suzhou, 215123, China
- 6Department of Anesthesiology, Second Affiliated Changzhou People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, China
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Author contributions: J.H., H.B., Z.Y., W.H., G.Z., and X.Z. performed research; J.H., H.B., and G.C. analyzed data; J.H. and Y.H. edited the paper; W.H., X.Z., Y.S.S., Y.S., Q.M., F.K., Y.H., and G.C. contributed unpublished reagents/analytic tools; Y.H. and G.C. designed research; G.C. wrote the paper.
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↵*J.H. and H.B. contributed equally to this work.
Abstract
Mutations on γ-secretase subunits are associated with neurologic diseases. Whereas the role of γ-secretase in neurogenesis has been intensively studied, little is known about its role in astrogliogenesis. Recent evidence has demonstrated that astrocytes can be generated from oligodendrocyte precursor cells (OPCs). However, it is not well understood what mechanism may control OPCs to differentiate into astrocytes. To address the above questions, we generated two independent lines of oligodendrocyte lineage-specific presenilin enhancer 2 (Pen-2) conditional KO mice. Both male and female mice were used. Here we demonstrate that conditional inactivation of Pen-2 mediated by Olig1-Cre or NG2-CreERT2 causes enhanced generation of astrocytes. Lineage-tracing experiments indicate that abnormally generated astrocytes are derived from Cre-expressing OPCs in the CNS in Pen-2 conditional KO mice. Mechanistic analysis reveals that deletion of Pen-2 inhibits the Notch signaling to upregulate signal transducer and activator of transcription 3, which triggers activation of GFAP to promote astrocyte differentiation. Together, these novel findings indicate that Pen-2 regulates the specification of astrocytes from OPCs through the signal transducer and activator of transcription 3 signaling.
SIGNIFICANCE STATEMENT Astrocytes and oligodendrocyte (OLs) play critical roles in the brain. Recent evidence has demonstrated that astrocytes can be generated from OL precursor cells (OPCs). However, it remains poorly understood what mechanism governs the differentiation of OPCs into astrocytes. In this study, we took advantage of OL lineage cells specific presenilin enhancer 2 (Pen-2) conditional KO mice. We show that deletion of Pen-2 leads to dramatically enhanced astrocyte differentiation from OPCs in the CNS. Mechanistic analysis reveals that deletion of Pen-2 inhibits Hes1 and activates signal transducer and activator of transcription 3 to trigger GFAP activation which promotes astrocyte differentiation. Overall, this study identifies a novel function of Pen-2 in astrogliogenesis from OPCs.
- astrocytes
- astrogliogenesis
- oligodendrocyte differentiation
- oligodendrocyte precursor cells
- Presenilin enhancer 2
- Received October 15, 2019.
- Revision received March 30, 2021.
- Accepted April 28, 2021.
- Copyright © 2021 the authors
