Mice that transiently overexpress a dominant negative fgfr1 gene that interferes with normal functioning of all receptor types during early embryogenesis have a smaller cortex, particularly in the frontal and temporal regions, and reduced numbers of excitatory neurons (Shin et al., 2004). Furthermore, these mice exhibited hyperactivity. Specific receptor knockouts have subsequently shown the relative contribution of each FGF receptor to cortical development. In order to avoid embryonic lethality of fgfr1 and fgfr2 systemic gene knockouts, fgfr alleles containing loxP site have been recombined in vivo with a variety of Cre lines, including the foxg1 knock-in Cre, nestin-Cre and hgfap-Cre lines. Mice lacking fgfr1 in radial glial progenitors driven by hgfap-Cre (which targets the dorsal telencephalon and hippocampal anlage), exhibited severe reduction of hippocampal volume, almost complete absence of midline telencephalic commissures due to abnormal development of midline glia, and decreased inhibitory interneuron number in the cortex and hippocampus (Ohkubo et al., 2004; Smith et al., 2006; Muller Smith et al., 2008). In contrast, the number of cortical excitatory neurons was not decreased in mice lacking fgfr1 alone (Muller Smith et al., 2008). However, mice lacking fgfr2 alone or in combination with fgfr1, via hgfap-Cre mediated recombination, showed a decrease in cortical excitatory neurons and volume, both of which were more pronounced in the medial prefrontal area of the cortex (Stevens et al., 2010). The mechanism of these abnormalities leading to a loss of cortical excitatory neurons resides in the ability of FGFR2 signaling to induce radial glial stem cells to re-enter the cell cycle, particularly in anterior regions. Therefore, FGFR2 support prefrontal cortical development by promoting the self-renewal or maintenance of cortical stem cells. These data converge with previous work demonstrating that PFC size is reduced by knockout of FGF17, a ligand for FGFR2 (Cholfin and Rubenstein, 2008).