BDNF/MAPK/ERK-induced BMP7 expression in the developing cerebral cortex induces premature radial glia differentiation and impairs neuronal migration.
During development of the mammalian nervous system, a combination of genetic and environmental factors governs the sequential generation of neurons and glia and the initial establishment of the neural circuitry. Here, we demonstrate that brain-derived neurotrophic factor (BDNF), one of those local acting factors, induces Bone Morphogenetic Protein 7 (BMP7) expression in embryonic neurons by activating Mitogen-Activated Protein Kinase/Extracellular signal-Regulated Kinase signaling and by the negative regulation of p53/p73 function. We also show that intraventricular injection of BMP7 at midgestation induces the early differentiation of radial glia into glial precursors and astrocytes and the expression of mature glial markers such as the antiadhesive protein SC1. As a result of this precocious radial glia maturation, the laminar distribution of late-born pyramidal neurons is altered, most likely by the termination of radial glia ability to support neuronal migration and the early neuronal detachment from the glial rail. We propose a mechanism for BDNF regulation of BMP7 in which local activity-driven BDNF-induced BMP7 expression at the end of neurogenesis instructs competent precursors to generate astrocytes. Such a mechanism might ensure synchronic neuronal and glial maturation at the beginning of cortical activity.
Ortega
Juan Alberto
JA
Unit of Cell Biology, Department of Experimental Pathology and Therapeutics, School of Medicine, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain.
Alcántara
Soledad
S
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7 / Q000096:biosynthesis* / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D055419:Bone Morphogenetic Protein 7; D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C525820:bmp7 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases