Abstract
During neurogenesis, complex networks of genes act sequentially to control neuronal differentiation. In the neural tube, the expression of Pax6, a paired-box-containing gene, just precedes the appearance of the first post-mitotic neurons. So far, its only reported function in the spinal cord is in specifying subsets of neurons. Here we address its possible function in controlling the balance between proliferation and commitment of neural progenitors. We report that increasing Pax6 level is sufficient to push neural progenitors toward cell cycle exit and neuronal commitment via Neurogenin 2 (Ngn2) upregulation. However, neuronal precursors maintaining Pax6(On) fail to perform neuronal differentiation. Conversely, turning off Pax6 function in these precursors is sufficient to provoke premature differentiation and the number of differentiated neurons depends of the amount of Pax6 protein. Moreover, we found that Pax6 expression involves negative feedback regulation by Ngn2 and this repression is critical for the proneural activity of Ngn2. We present a model in which the level of Pax6 activity first conditions the moment when a given progenitor will leave the cell cycle and second, the moment when a selected neuronal precursor will irreversibly differentiate.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors
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Basic Helix-Loop-Helix Transcription Factors / biosynthesis
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Cell Cycle / physiology
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Cell Differentiation / genetics
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Cell Differentiation / physiology*
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Chick Embryo
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Eye Proteins / antagonists & inhibitors
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Eye Proteins / biosynthesis
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Eye Proteins / physiology*
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Gene Expression Regulation, Developmental / physiology
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Homeodomain Proteins / antagonists & inhibitors
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Homeodomain Proteins / biosynthesis
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Homeodomain Proteins / physiology*
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Mice
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / biosynthesis
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Nerve Tissue Proteins / genetics
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Neurons / cytology*
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Neurons / metabolism
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PAX6 Transcription Factor
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Paired Box Transcription Factors / antagonists & inhibitors
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Paired Box Transcription Factors / biosynthesis
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Paired Box Transcription Factors / physiology*
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / biosynthesis
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Repressor Proteins / physiology*
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Spinal Cord / cytology
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Spinal Cord / embryology*
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Spinal Cord / physiology
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Stem Cells / cytology
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Stem Cells / metabolism
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Time Factors
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Eye Proteins
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Homeodomain Proteins
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Nerve Tissue Proteins
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Neurog2 protein, mouse
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PAX6 Transcription Factor
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Paired Box Transcription Factors
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Pax6 protein, mouse
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Repressor Proteins