Abstract
The development of the brain requires the exquisite coordination of progenitor proliferation and differentiation to achieve complex circuit assembly. It has been suggested that glycogen synthase kinase 3 (GSK-3) acts as an integrating molecule for multiple proliferation and differentiation signals because of its essential role in the RTK, Wnt and Shh signaling pathways. We created conditional mutations that deleted both the alpha and beta forms of GSK-3 in mouse neural progenitors. GSK-3 deletion resulted in massive hyperproliferation of neural progenitors along the entire neuraxis. Generation of both intermediate neural progenitors and postmitotic neurons was markedly suppressed. These effects were associated with the dysregulation of beta-catenin, Sonic Hedgehog, Notch and fibroblast growth factor signaling. Our results indicate that GSK-3 signaling is an essential mediator of homeostatic controls that regulate neural progenitors during mammalian brain development.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bromodeoxyuridine / metabolism
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Cell Differentiation / physiology
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Cell Proliferation
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Cells, Cultured
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Embryo, Mammalian
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Gene Expression Regulation, Developmental
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Glycogen Synthase Kinase 3 / classification
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Glycogen Synthase Kinase 3 / deficiency
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Glycogen Synthase Kinase 3 / physiology*
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Homeostasis / genetics
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Homeostasis / physiology*
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Humans
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Intermediate Filament Proteins / genetics
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Mice
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Mice, Knockout
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Mutation / genetics
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Neocortex / cytology
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Neocortex / embryology
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nestin
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Neurons / physiology*
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Signal Transduction / genetics
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Signal Transduction / physiology
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Stem Cells / physiology*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transfection / methods
Substances
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Intermediate Filament Proteins
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NES protein, human
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Nerve Tissue Proteins
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Nes protein, mouse
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Nestin
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Transcription Factors
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Glycogen Synthase Kinase 3
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Bromodeoxyuridine