FGFR3 regulates brain size by controlling progenitor cell proliferation and apoptosis during embryonic development.
Mice with the K644E kinase domain mutation in fibroblast growth factor receptor 3 (Fgfr3) (EIIa;Fgfr3(+/K644E)) exhibited a marked enlargement of the brain. The brain size was increased as early as E11.5, not secondary to the possible effect of Fgfr3 activity in the skeleton. Furthermore, the mutant brains showed a dramatic increase in cortical thickness, a phenotype opposite to that in FGF2 knockout mice. Despite this increased thickness, cortical layer formation was largely unaffected and no cortical folding was observed during embryonic days 11.5-18.5 (E11.5-E18.5). Measurement of cortical thickness revealed an increase of 38.1% in the EIIa;Fgfr3(+/K644E) mice at E14.5 and the advanced appearance of the cortical plate was frequently observed at this stage. Unbiased stereological analysis revealed that the volume of the ventricular zone (VZ) was increased by more than two fold in the EIIa;Fgfr3(+/K644E) mutants at E14.5. A relatively mild increase in progenitor cell proliferation and a profound decrease in developmental apoptosis during E11.5-E14.5 most likely accounts for the dramatic increase in total telecephalic cell number. Taken together, our data suggest a novel function of Fgfr3 in controlling the development of the cortex, by regulating proliferation and apoptosis of cortical progenitors.
Inglis-Broadgate
Suzanne L
SL
Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Beatson Laboratories for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK.
Thomson
Rachel E
RE
Pellicano
Francesca
F
Tartaglia
Michael A
MA
Pontikis
Charlie C
CC
Cooper
Jonathan D
JD
Iwata
Tomoko
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D002455:Cell Division; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D003001:Cloning, Molecular; D047108:Embryonic Development; D005865:Gestational Age; D020287:In Situ Nick-End Labeling; D051379:Mice; D016296:Mutagenesis; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology*
D017468:Receptors, Fibroblast Growth Factor; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3