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

Abstract

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 ϳ30% decrease in dividing radial glial progenitor cells in the hippocampal VZ and DG in the late embryonic period, progressing to a ϳ50 -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 ϳ30 -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.

Early Postnatal Astroglial Cells Produce Multilineage Precursors and Neural Stem CellsIn Vivo

“…As expected, the GCE transgene targeted recombination to radial glial cells when induced during embryogenesis, consistent with previous findings using the hGFAPCre line (Malatesta et al, 2003;Ohkubo et al, 2004;Casper and McCarthy, 2006), whereas during the first postnatal week, GCE targeted recombination to GFAP ϩ /RC1 ϩ astroglial cells of various morphologies, but not in neurons or oligodendrocytes (Table 1). In the P8 SVZ, hippocampus, and cortex, nearly all reporter ϩ cells expressed LeX, an antigen also expressed by embryonic and adult NSCs (Capela and Temple, 2002) and the great majority were immunoreactive for GFAP ϩ and RC1, yet in each area we observed a small population (10 -20%) of unlabeled cells.…”

FGF-2 Overexpression Increases Excitability and Seizure Susceptibility but Decreases Seizure-Induced Cell Loss

“…To evaluate whether FGF-2 overexpression changed FGF receptor density, we used immunohistochemistry to analyze the distribution of FGFR1, the FGF receptor subtype most expressed in the hippocampus (Ohkubo et al, 2004). Consistent with previous reports in rats and humans Weickert et al, 2005), FGFR1 immunoreactivity was found in putative pyramidal neurons of CA1, CA2 and CA3 pyramidal region in WT mice.…”

Evidence‐Based Theory for Integrated Genome Regulation of Ontogeny—An Unprecedented Role of Nuclear FGFR1 Signaling

“…For instance in proliferating brain stem cells FGFR1 is cytoplasmic whereas in differentiating neural cells FGFR1 accumulates in the cell nucleus (Stachowiak et al, 2012a). In agreement with this dual distribution, brain‐targeted FGFR1 knockout impairs both the cell proliferation and differentiation (Pirvola et al, 2002; Ohkubo et al, 2004) which may reflect the loss of FGFR1 signaling at the cell surface and the INFS, respectively (Stachowiak et al, 2012b). …”