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The Journal of Neuroscience, July 7, 2004, 24(27):6057-6069; doi:10.1523/JNEUROSCI.1140-04.2004

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Development/Plasticity/Repair
Fibroblast Growth Factor Receptor 1 Is Required for the Proliferation of Hippocampal Progenitor Cells and for Hippocampal Growth in Mouse

Yasushi Ohkubo,¹ Ayumi O. Uchida,¹ Dana Shin,¹ Juha Partanen,² and Flora M. Vaccarino¹

¹Child Study Center, Yale University, New Haven, Connecticut 06520, and ²Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland

Fibroblast growth factor receptor 1 (Fgfr1) is expressed at high levels by progenitor cells of the ventricular zone (VZ) within the hippocampal primordium. To investigate the role of Fgfr1 in these cells, in vivo Cre recombination of "floxed" Fgfr1 alleles was directed to cells of the radial glial lineage by using the human glial fibrillary acidic protein promoter. Radial glial-like cells of the hippocampal VZ are the progenitors of pyramidal neurons and granule cells of hippocampal dentate gyrus (DG). Mice carrying null Fgfr1 alleles (Fgfr1^flox) in cells of this lineage showed a dramatic loss of Fgfr1 gene expression throughout the embryonic dorsal telencephalon. These Fgfr1^flox mice exhibited a 30% decrease in dividing radial glial progenitor cells in the hippocampal VZ and DG in the late embryonic period, progressing to a 50-60% loss at birth, without any changes in cell survival. In addition, no FGF2-sensitive neural stem cells could be isolated from the Fgfr1^flox hippocampal neuroepithelium, whereas epidermal growth factor-sensitive neural stem cells were not affected. The number of hippocampal pyramidal neurons and DG granule cells was 30-50% decreased from the perinatal period through adulthood, and the number of parvalbumin-containing interneurons was similarly decreased in both the DG and pyramidal cell fields. We conclude that Fgfr1 is necessary for hippocampal growth, because it promotes the proliferation of hippocampal progenitors and stem cells during development.

Key words: mouse; progenitor; neural stem cell; FGF; growth factor; tyrosine kinase; radial glia

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Received Sep 7, 2003; revised May 18, 2004; accepted May 18, 2004.

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