Abstract
The processes regulating cortical surface area expansion during development and evolution are unknown. We show that loss of function of all fibroblast growth factor receptors (FgfRs) expressed at the earliest stages of cortical development causes severe deficits in surface area growth by embryonic day 12.5 (E12.5) in the mouse. In FgfR mutants, accelerated production of neurons led to severe loss of radial progenitors and premature termination of neurogenesis. Nevertheless, these mutants showed remarkably little change in cortical layer structure. Birth-dating experiments indicated that a greater proportion of layer fates was generated during early neurogenic stages, revealing that FgfR activity normally slows the temporal progression of cortical layer fates. Electroporation of a dominant-negative FgfR at E11.5 increased cortical neurogenesis in normal mice--an effect that was blocked by simultaneous activation of the Notch pathway. Together with changes in the expression of Notch pathway genes in FgfR mutant embryos, these findings indicate that Notch lies downstream of FgfR signaling in the same pathway regulating cortical neurogenesis and begin to establish a mechanism for regulating cortical surface expansion.
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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Age Factors
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Analysis of Variance
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Animals
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Brain / cytology
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Brain / embryology
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Brain / metabolism
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Bromodeoxyuridine / metabolism
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Caspase 3 / metabolism
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Cell Count
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Cell Differentiation / genetics
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Cells, Cultured
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Cerebral Cortex / cytology*
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Cerebral Cortex / embryology
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Cerebral Cortex / metabolism*
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DNA-Binding Proteins / metabolism
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Electroporation / methods
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Embryo, Mammalian
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Eye Proteins / metabolism
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Fatty Acid-Binding Protein 7
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Fatty Acid-Binding Proteins / genetics
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / metabolism*
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Gene Expression Regulation, Developmental / genetics
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Green Fluorescent Proteins / genetics
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Ki-67 Antigen / metabolism
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Mice
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Mice, Transgenic
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Mutation / genetics
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Nerve Tissue Proteins / genetics
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Neurogenesis / genetics
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Neurogenesis / physiology*
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Neurons / physiology*
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PAX6 Transcription Factor
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Paired Box Transcription Factors / metabolism
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Receptors, Fibroblast Growth Factor / genetics
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Receptors, Notch / genetics
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Receptors, Notch / metabolism*
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Repressor Proteins / metabolism
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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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T-Box Domain Proteins / metabolism
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Transcription Factors / genetics
Substances
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DNA-Binding Proteins
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Eomes protein, mouse
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Eye Proteins
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Fabp7 protein, mouse
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Fatty Acid-Binding Protein 7
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Fatty Acid-Binding Proteins
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Homeodomain Proteins
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Ki-67 Antigen
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Nerve Tissue Proteins
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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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Receptors, Fibroblast Growth Factor
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Receptors, Notch
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Repressor Proteins
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T-Box Domain Proteins
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Tbr1 protein, mouse
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Transcription Factors
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empty spiracles homeobox proteins
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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Fibroblast Growth Factors
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Caspase 3
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Bromodeoxyuridine