Decrease in excitatory neurons, astrocytes and proliferating progenitors in the cerebral cortex of mice lacking exon 3 from the Fgf2 gene.
BACKGROUND
The Fgf2 gene is expressed in the brain neuroepithelium during embryonic development and in astroglial cells throughout life. Previous knockout studies suggested that FGF2 plays a role in the proliferation of neural progenitors in the embryonic cerebral cortex. These studies exclusively used knockout alleles lacking the Fgf2 exon 1. However, the description of putative alternative exons located downstream from the canonical exon 1 raised the possibility that alternatively spliced transcripts may compensate for the lack of the canonical exon 1 in the Fgf2 -/- mice.


RESULTS
We generated and characterized a new line of Fgf2 knockout mice lacking the expression of exon 3, which is conserved in all Fgf2 transcripts and contains essential heparin and receptor binding interfaces. The expression of Fgf2 exon 3 was prevented by inserting a transcriptional STOP cassette in the Fgf2 genomic locus. These mice demonstrate a phenotype in the adult neocortex characterized by decreased density and number of cortical excitatory neurons and astrocytes, which is virtually identical to that of the Fgf2 -/- mice lacking exon 1. In addition, we also show that the Fgf2 exon 3 knockout mice have decreased proliferation of precursors in the adult cerebral cortex, which had not been previously investigated in the other mutant lines.


CONCLUSIONS
The results demonstrate that the phenotype of two completely different Fgf2 KO mouse lines, lacking exon 1 or exon 3, is remarkably similar. The combined results from these KO models clearly indicate that FGF2 plays a role in cortical cell genesis during embryonic development as well as in adulthood. Thus, FGF2 may be required for the maintenance of the pool of adult cortical progenitor cells.
Chen
Kesi
K
Child Study Center, Yale University School of Medicine, 230 South Frontage Rd, New Haven, CT 06520, USA. kesi.chen@yale.edu
Ohkubo
Yasushi
Y
Shin
Dana
D
Doetschman
Thomas
T
Sanford
L Philip
LP
Li
Hongqi
H
Vaccarino
Flora M
FM
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D005091:Exons; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
D016222:Fibroblast Growth Factor 2