Fibroblast growth factor receptor 3 kinase domain mutation increases cortical progenitor proliferation via mitogen‐activated protein kinase activation
Copyright policy )Fibroblast growth factor receptor 3 kinase domain mutation increases cortical progenitor proliferation via mitogen‐activated protein kinase activation
AbstractWe have previously shown that mice carrying the K644E kinase domain mutation in fibroblast growth factor receptor 3 (Fgfr3) (EIIa;Fgfr3+/K644E) have enlarged brains with increased proliferation and decreased apoptosis of the cortical progenitors. Despite its unique rostral‐low caudal‐high gradient expression in the cortex, how Fgfr3 temporally and spatially influences progenitor proliferation is unknown. In vivo BrdU labelling now showed that progenitor proliferation was 10–46% higher in the EIIa;Fgfr3+/K644E cortex compared with wild type during embryonic day 11.5 (E11.5)–E13.5. The difference in proliferation between the EIIa;Fgfr3+/K644E and wild‐type cortices was the greatest in the caudal cortex at E12.5 and E13.5. Inhibition of mitogen‐activated or extracellular signal‐regulated protein kinase (MEK) in vitro at E11.5 reduced the proliferation rate of the EIIa;Fgfr3+/K644E cortical progenitors to similar levels observed in the wild type, indicating that the majority of the increase in cell proliferation caused by the Fgfr3 mutation is mitogen‐activated protein kinase (MAPK) pathway‐dependent at this stage. In addition, elevated levels of Sprouty were observed in the EIIa;Fgfr3+/K644E telencephalon at E14.5, indicating the presence of negative feedback that may have suppressed further MAPK activation. We suggest that temporal activation of MAPK is largely responsible for cell proliferation caused by the Fgfr3 mutation during early stages of cortical development.
- University of Glasgow United Kingdom
Cerebral Cortex, Reverse Transcriptase Polymerase Chain Reaction, Age Factors, Gene Expression Regulation, Developmental, Mice, Transgenic, Embryo, Mammalian, Protein Structure, Tertiary, Enzyme Activation, Mice, Inbred C57BL, Mice, Bromodeoxyuridine, Pregnancy, Mutation, Animals, Receptor, Fibroblast Growth Factor, Type 3, Female, Mitogen-Activated Protein Kinases, Cells, Cultured, In Situ Hybridization, Cell Proliferation
Cerebral Cortex, Reverse Transcriptase Polymerase Chain Reaction, Age Factors, Gene Expression Regulation, Developmental, Mice, Transgenic, Embryo, Mammalian, Protein Structure, Tertiary, Enzyme Activation, Mice, Inbred C57BL, Mice, Bromodeoxyuridine, Pregnancy, Mutation, Animals, Receptor, Fibroblast Growth Factor, Type 3, Female, Mitogen-Activated Protein Kinases, Cells, Cultured, In Situ Hybridization, Cell Proliferation
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