AKT activation by N-cadherin regulates beta-catenin signaling and neuronal differentiation during cortical development
Open accessAbstract
Background: During cerebral cortical development, neural precursor-precursor interactions in the ventricular zone neurogenic niche coordinate signaling pathways that regulate proliferation and differentiation. Previous studies with shRNA knockdown approaches indicated that N-cadherin adhesion between cortical precursors regulates β-catenin signaling, but the underlying mechanisms remained poorly understood. Results: Here, with conditional knockout approaches, we find further supporting evidence that N-cadherin maintains β-catenin signaling during cortical development. Using shRNA to N-cadherin and dominant negative N-cadherin overexpression in cell culture, we find that N-cadherin regulates Wnt-stimulated β-catenin signaling in a cell-autonomous fashion. Knockdown or inhibition of N-cadherin with function-blocking antibodies leads to reduced activation of the Wnt co-receptor LRP6. We also find that N-cadherin regulates β-catenin via AKT, as reduction of N-cadherin causes decreased AKT activation and reduced phosphorylation of AKT targets GSK3β and β-catenin. Inhibition of AKT signaling in neural precursors in vivo leads to reduced β-catenin-dependent transcriptional activation, increased migration from the ventricular zone, premature neuronal differentiation, and increased apoptotic cell death. Conclusions: These results show that N-cadherin regulates β-catenin signaling through both Wnt and AKT, and suggest a previously unrecognized role for AKT in neuronal differentiation and cell survival during cortical development.
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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 [89]
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- Authors
- Zhang, J., Shemezis, J. R., McQuinn, E. R., Wang, J., Sverdlov, M., & Chenn, A.
- Affiliations
- Northwestern University (US)
- University of Illinois Chicago (US)
- Corresponding author
- Chenn, Anjen
- Venue
- Neural Development
- Published
- 2013-04-25
- Volume
- 8
- Issue
- 1
- Pages
- 7-7
- ISSN
- 1749-8104 (ISSN-L)
- PMC
- PMC3658902
- OpenAlex
- W2165383481
- Cited by
- 107
- References
- 55
- Citations by year
- 2025: 4 · 2024: 10 · 2023: 4 · 2022: 12 · 2021: 9 · 2020: 7 · 2019: 6 · 2018: 14 · 2017: 8 · 2016: 17 · 2015: 9 · 2014: 7
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Neural Development (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Coleman Foundation
- March of Dimes Foundation
- Aflac
- Emory University
- Northwestern University
- Children's Healthcare of Atlanta
- National Institutes of Health
- University of Illinois at Urbana-Champaign
- Feinberg School of Medicine
- National Cancer Institute (R21CA149388)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- N-cadherin, Akt signaling, β-catenin signaling, Wnt signaling, GSK3β phosphorylation, neuronal differentiation, cortical development, neuronal precursors, ventricular zone, cell adhesion, apoptosis, conditional knockout
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Brain, Cell Differentiation, Cells, Cultured, Enzyme Activation, Mice, Inbred C57BL, Neurons, Signal Transduction, Cadherins, Glycogen Synthase Kinase 3, Proto-Oncogene Proteins c-akt, Wnt Proteins, beta Catenin, Mice, Gene Knockdown Techniques
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