Context-dependent regulation of Notch signaling in glial development and tumorigenesis

In the mammalian brain, Notch signaling maintains the cortical stem cell pool and regulates the glial cell fate choice and differentiation. However, the function of Notch in regulating glial development and its involvement in tumorigenesis have not been well understood. Here, we show that Notch inac...

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Bibliographic Details
Published in:Science advances 2023-11, Vol.9 (45), p.eadi2167-eadi2167
Main Authors: Guo, Rongliang, Han, Danyu, Song, Xingrui, Gao, Yanjing, Li, Zhenmeiyu, Li, Xiaosu, Yang, Zhengang, Xu, Zhejun
Format: Article
Language:English
Subjects:
Animals
Carcinogenesis - genetics
Cell Differentiation - genetics
Cell Transformation, Neoplastic - genetics
Glioma - genetics
Mammals - metabolism
Neurogenesis - genetics
Neuroglia - metabolism
Neuroscience
Receptors, Notch - genetics
Receptors, Notch - metabolism
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Summary:In the mammalian brain, Notch signaling maintains the cortical stem cell pool and regulates the glial cell fate choice and differentiation. However, the function of Notch in regulating glial development and its involvement in tumorigenesis have not been well understood. Here, we show that Notch inactivation by genetic deletion of in stem cells decreases astrocytes but increases oligodendrocytes with altered internal states. Inhibiting Notch in glial progenitors does not affect cell generation but instead accelerates the growth of Notch-deprived oligodendrocyte progenitor cells (OPCs) and OPC-related glioma. We also identified a cross-talk between oligodendrocytes and astrocytes, with premyelinating oligodendrocytes secreting BMP4, which is repressed by Notch, to up-regulate GFAP expression in adjacent astrocytes. Moreover, Notch inactivation in stem cells causes a glioma subtype shift from astroglia-associated to OPC-correlated patterns and vice versa. Our study reveals Notch's context-dependent function, promoting astrocytes and astroglia-associated glioma in stem cells and repressing OPCs and related glioma in glial progenitors.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adi2167