Abstract
The lack of fragile X mental retardation protein (FMRP) causes fragile X syndrome, a common form of inherited mental retardation. Our previous studies revealed alterations in the differentiation of FMRP-deficient neural progenitors. Here, we show abnormalities in neurogenesis in the mouse and human embryonic FMRP-deficient brain as well as after in utero transfection of I304N mutated FMRP, which acts in a dominant negative manner in the wild-type mouse brain. Progenitors accumulated abnormally in the subventricular zone of the embryonic Fmr1-knockout (Fmr1-KO) mouse neocortex. An increased density of cells expressing sequentially an intermediate progenitor marker, T-box transcription factor (Tbr2), and a postmitotic neuron marker, T-brain 1 (Tbr1), indicated that the differentiation to glutamatergic cell lineages was particularly disturbed. These abnormalities were associated with an increased density of pyramidal cells of the layer V in the early postnatal neocortex suggesting a role for FMRP in the regulation of the differentiation of neocortical glutamatergic neurons.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Cell Differentiation
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Cell Lineage
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DNA-Binding Proteins / metabolism
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Disease Models, Animal
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Excitatory Amino Acid Transporter 1 / metabolism
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Fatty Acid-Binding Protein 7
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Fatty Acid-Binding Proteins / metabolism
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Fragile X Mental Retardation Protein / genetics*
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Fragile X Mental Retardation Protein / physiology
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Fragile X Syndrome / embryology
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Fragile X Syndrome / genetics
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Fragile X Syndrome / pathology
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Fragile X Syndrome / physiopathology*
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Glutamic Acid / metabolism*
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Mesenchymal Stem Cells / metabolism
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Mice
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Mice, Knockout
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Mutation
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Neocortex / embryology*
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Neocortex / pathology
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Neocortex / physiopathology
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Nerve Tissue Proteins / metabolism
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Neurogenesis*
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Neurons / cytology
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Neurons / metabolism*
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Pyramidal Cells / growth & development
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Stem Cells / cytology*
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T-Box Domain Proteins / metabolism
Substances
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DNA-Binding Proteins
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Eomes protein, mouse
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Excitatory Amino Acid Transporter 1
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FMR1 protein, human
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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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Fmr1 protein, mouse
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Nerve Tissue Proteins
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Slc1a3 protein, mouse
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T-Box Domain Proteins
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Tbr1 protein, mouse
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Fragile X Mental Retardation Protein
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Glutamic Acid