Abstract
The balance between self-renewal and differentiation of neural progenitor cells is an absolute requirement for the correct formation of the nervous system. Much is known about both the pathways involved in progenitor cell self-renewal, such as Notch signaling, and the expression of genes that initiate progenitor differentiation. However, whether these fundamental processes are mechanistically linked, and specifically how repression of progenitor self-renewal pathways occurs, is poorly understood. Nuclear factor I A (Nfia), a gene known to regulate spinal cord and neocortical development, has recently been implicated as acting downstream of Notch to initiate the expression of astrocyte-specific genes within the cortex. Here we demonstrate that, in addition to activating the expression of astrocyte-specific genes, Nfia also downregulates the activity of the Notch signaling pathway via repression of the key Notch effector Hes1. These data provide a significant conceptual advance in our understanding of neural progenitor differentiation, revealing that a single transcription factor can control both the activation of differentiation genes and the repression of the self-renewal genes, thereby acting as a pivotal regulator of the balance between progenitor and differentiated cell states.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Age Factors
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Analysis of Variance
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Bromodeoxyuridine / metabolism
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Cell Count / methods
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Cell Differentiation / genetics*
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Cerebral Ventricles / cytology
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Cerebral Ventricles / embryology
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Chromatin Immunoprecipitation / methods
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Electrophoretic Mobility Shift Assay / methods
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Embryo, Mammalian
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Gene Expression Regulation, Developmental / genetics
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Gene Expression Regulation, Developmental / physiology*
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Hippocampus / cytology
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Hippocampus / growth & development
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microarray Analysis / methods
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Mutation / genetics
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NFI Transcription Factors / deficiency
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NFI Transcription Factors / physiology*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Octamer Transcription Factor-6 / genetics
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Octamer Transcription Factor-6 / metabolism
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Promoter Regions, Genetic / physiology
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Receptors, Kainic Acid / genetics
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Receptors, Kainic Acid / metabolism
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Stem Cells / physiology*
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Telencephalon / cytology*
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Telencephalon / embryology
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Transcription Factor HES-1
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Grik4 protein, mouse
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Hes1 protein, mouse
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Homeodomain Proteins
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NFI Transcription Factors
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Nerve Tissue Proteins
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Nfia protein, mouse
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Pou3f1 protein, mouse
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Receptors, Kainic Acid
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Transcription Factor HES-1
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Tumor Suppressor Proteins
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prospero-related homeobox 1 protein
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Octamer Transcription Factor-6
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Bromodeoxyuridine