TY - JOUR
T1 - FGFR3 regulates brain size by controlling progenitor cell proliferation and apoptosis during embryonic development
AU - Inglis-Broadgate, Suzanne L.
AU - Thomson, Rachel E.
AU - Pellicano, Francesca
AU - Tartaglia, Michael A.
AU - Pontikis, Charlie C.
AU - Cooper, Jonathan D.
AU - Iwata, Tomoko
N1 - Funding Information:
We thank Biological Services, Molecular Technology, and Technology Services of the Beatson Laboratories for Cancer Research, for their support in animal care, genotyping, and in histology, respectively. We also thank Drs. Sue Barnett and Lynda Chang for critical reading of the manuscript and other members of the PSDL for their kind support. This work was supported by grant BBS/B/08736 from the Biotechnology and Biological Science Research Council (to T.I). The microscopy equipment and sterology software in the PSDL was funded by National Institutes of Health grants NS41930 and NS44310 (JDC), a European Commission 6th Framework Research Grant LSHM-CT-2003-503051 (JDC), and grants to JDC from The Natalie Fund, Batten Disease Support and Research Association, Batten Disease Family Association and the Remy Fund.
PY - 2005/3/1
Y1 - 2005/3/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Brain size
KW - Cell proliferation
KW - Cortical development
KW - Cortical progenitors
KW - FGF
KW - FGFR3
KW - Mouse
UR - http://www.scopus.com/inward/record.url?scp=13544257266&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2004.11.035
DO - 10.1016/j.ydbio.2004.11.035
M3 - Article
C2 - 15708559
AN - SCOPUS:13544257266
SN - 0012-1606
VL - 279
SP - 73
EP - 85
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -