Cell type-dependent Erk-Akt pathway crosstalk regulates the proliferation of fetal neural progenitor cells
Open accessAbstract
Neural progenitor (NP) cells are the multipotent cells that produce neurons and glia in the central nervous system. Compounds regulating their proliferation are key to both understanding brain development and unlocking their potential in regenerative repair. We discuss a chemical screen that unexpectedly identified inhibitors of Erk signaling potently promoting the self-renewing divisions of fetal NP cells. This occurred through crosstalk between Erk and Akt signaling cascades. The crosstalk mechanism is cell type-specific and is not detected in adult NP cells as well as brain tumor cells. The mechanism was also shown to be independent from the GSK-3 signaling pathway, which has been reported to be a major regulator of NP cell homeostasis and inhibitors to which were also identified in the screen. In vitro Erk inhibition led to the prolonged rapid expansion of fetal NP cells while retaining their multipotency. In vivo inhibitor administration significantly inhibited the neuronal differentiation and resulted in increased proliferative progenitor cells in the ventricular/subventricular zone (VZ/SVZ) of the embryonic cortex. Our results uncovered a novel regulating pathway for NP cell proliferation in the developing brain. The discovery provides a pharmacological basis for in vitro expansion and in vivo manipulation of NP cells.
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Induced proliferation by signaling pathways can result in either a thicker or thinner cortex in mouse models depending on the strength of the dysregulation.
“the induced proliferation by the signaling pathways can result in either a thicker or thinner cortex in mice models depending on the strength of the dysregulation.”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [86]
Downregulation of RAS/ERK can lead to a thicker cortex from increased proliferation and an increased neuronal count.
“While downregulation of RAS/ERK can lead to a thicker cortex from increased proliferation and an increased neuronal count [86]”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [86]
In precursor and radial glial cells (RGCs), upregulation of PI3K/AKT, WNT and β-catenin or downregulation of RAS/ERK leads to elevated proliferation.
“In precursor and radial glial cells (RGCs), upregulation of PI3K/AKT, WNT and β-catenin or downregulation of RAS/ERK leads to elevated proliferation [86, 88, 89].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [86]
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The ASD Living Biology: from cell proliferation to clinical phenotype
Courchesne, E., Pramparo, T., Gazestani, V. H., Lombardo, M. V., Pierce, K., & Lewis, N. E. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0056-y · Cited by 333 · see citing works
- Authors
- Rhim, J. H., Luo, X., Gao, D., Xu, X., Zhou, T., Li, F., Wang, P., Wong, S. T. C., & Xia, X.
- Affiliations
- Houston Methodist (US)
- Corresponding author
- Xia, Xiaofeng
- Venue
- Scientific Reports
- Published
- 2016-05-23
- Volume
- 6
- Issue
- 1
- Pages
- 26547-26547
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4876380
- OpenAlex
- W2402416000
- Cited by
- 42
- References
- 53
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 10 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 1
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R21AG042585)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- neural progenitor cells, ERK signaling, Akt signaling, signaling crosstalk, cell proliferation, fetal brain development, ERK inhibitor, glycogen synthase kinase-3, neuronal differentiation, ventricular-subventricular zone, multipotency, self-renewal, chemical screen
- MeSH terms
- Animals, Cell Communication, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Humans, MAP Kinase Signaling System, Protein Kinase Inhibitors, Cell Proliferation, Proto-Oncogene Proteins c-akt, Rats, Embryonic Stem Cells, Neural Stem Cells
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