The Role of Fibroblast Growth Factor Receptors in the Morphogenesis and Maturation of the Neocortex

Fibroblast growth factors (Fgf) establish the primary structure of the cerebral cortex by controlling the self-renewal of stem cells and the surface expansion of the cerebral cortex and the hippocampus. Loss-of-function studies showed that Fgf2 expands cortical surface area (Vaccarino et al, 1999) by promoting neural stem cell self-renewal (Raballo et al, 2000). An Fgf2 microinjection in the embryonic mouse cerebral ventricles causes expansion of anterior cortical areas with symmetrical appearance of gyri/sulci in the normally smooth mouse cortex (Rash et al, 2013). Reduction of all Fgf receptor signaling in early neurogenesis depletes the stem cell pool resulting in premature ending of neurogenesis and decreased cortical surface area (Rash et al, 2011). Single Fgf receptors play more specific roles, Fgfr2 contributing to volume expansion of the prefrontal cortex (Stevens et al, 2010) and Fgfr1 of the hippocampus (Ohkubo et al, 2004).

Knockdown of FGF signaling in mouse cortical progenitors. In utero electroporation of a dominant negative FgfR1 in radial glia (green) of the developing mouse cerebral cortex accelerates cell cycle exit of neuronal daughter cells. In red are Ki67+ germinal zone cells.

A single intraventricular FGF2 injection in mice at the beginning of corticogenesis (E11) induces formation of bilateral sulci/gyri (arrows) evident in late embryos. Neo = neocortex; ins = insular cortex; pir = piriform cortex.

Enlargement of frontal brain regions and bilateral sulci/gyri (marked with *) persist in adulthood after intraventricular FGF2 injection in mouse embryos. A, 3D reconstruction; B, cresyl violet section; C, staining for CUX1 (green) and SMI32 (red).