Fibroblast growth factor receptor 3 kinase domain mutation increases cortical progenitor proliferation via mitogen-activated protein kinase activation.
We 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.
Thomson
Rachel E
RE
Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Beatson Laboratories for Cancer Research, Glasgow, UK.
Pellicano
Francesca
F
Iwata
Tomoko
T
D000367:Age Factors; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D017403:In Situ Hybridization / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D011247:Pregnancy; D017434:Protein Structure, Tertiary / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013234:Stem Cells / Q000502:physiology*
C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3; D020928:Mitogen-Activated Protein Kinases; D001973:Bromodeoxyuridine