Fibroblast Growth Factor 2 Is Necessary for the Growth of Glutamate Projection Neurons in the Anterior Neocortex

Abstract

Basic fibroblast growth factor (Fgf2) is required for the generation of founder cells within the dorsal pseudostratified ventricular epithelium, which will generate the cerebral cortex, but the ganglionic eminences are not affected. We report here that the Fgf2 null mutant mice show an ϳ40% decrease in cortical glutamatergic pyramidal neurons. In contrast, no change in pyramidal or granule cell number is detected in the hippocampus of Fgf2 Ϫ/Ϫ mice. In addition, the soma of the pyramidal cells in the frontal and parietal cortices are smaller in Fgf2 knock-out mice. The decrease in the number and size of glutamatergic neuronal population affects all cortical layers but is restricted to the frontal and parietal cortices without any change in the occipital cortex, indicating that Fgf2 is necessary to regulate cell number and size in the anterior cerebral cortex. In contrast to pyramidal neurons, cortical GABA interneurons are unaffected by the lack of Fgf2. The resulting imbalance between the excitatory and inhibitory neurotransmission in the cerebral cortex is reflected by an increased duration of sleep when the animals receive a GABA receptor agonist. Thus, Fgf2 signaling may contribute to the regional specification of the cerebral cortex and may play a role in increasing the size of anterior cortical regions during vertebrate evolution.

Self-Renewing and Differentiating Properties of Cortical Neural Stem Cells Are Selectively Regulated by Basic Fibroblast Growth Factor (FGF) Signaling via Specific FGF Receptors

“…Interestingly, inactivation of these FGFRs sustains a compartment of self-renewing GLAST ϩ MPNSCs whose survival may instead depend on epidermal growth factor and its receptors, which are expressed by a small fraction of cortical NSCs at E13 (Maric et al, 2003). Together, our findings emphasize the critical role of bFGF/FGFR signaling during the onset of neurogenesis in the rat cortex, and may explain the results obtained with transgenic mice and other in vitro studies that have demonstrated critical roles for bFGF and FGFRs in the expansion of NEPs, including putative NSCs and/or neural progenitors (Qian et al, 1997;Vaccarino et al, 1999;Raballo et al, 2000;Korada et al, 2002, Shin et al, 2004Inglis-Broadgate et al, 2005;Fortin et al, 2005). However, the identities of the earliest-born neurons derived from GLAST Ϫ NSCs and GLAST ϩ NSCs as putative pioneer neurons and Cajal-Retzius neurons, which emerge at the beginning of neurogenesis in the rat (Meyer et al, 1998), remain to be established.…”

“…One proposed mechanism critical to NSC biology involves the activity of basic fibroblast growth factor (bFGF) because transgenic mice devoid of bFGF are missing half the NEP population when neurogenesis begins, subsequently leading to a dramatic decrease of glutamatergic cortical neurons in the adult brain (Vaccarino et al, 1999;Raballo et al, 2000;Korada et al, 2002). A similar phenotype occurs when NEPs conditionally over-express a tyrosine kinase domain-deficient FGF receptor (Fgfr1) gene (Shin et al, 2004), thus implicating bFGF/FGFR1-mediated signaling in NEP expansion and, in time, generation of glutamatergic neurons.…”

Canonical Transient Receptor Potential 1 Plays a Role in Basic Fibroblast Growth Factor (bFGF)/FGF Receptor-1-Induced Ca2+ Entry and Embryonic Rat Neural Stem Cell Proliferation

“…bFGF also plays important roles in cortical neuroepithelial cell proliferation in vitro and in vivo (Vaccarino et al, 1995(Vaccarino et al, , 1999aDono et al, 1998;Ortega et al, 1998;Raballo et al, 2000;Korada et al, 2002). A major receptor for bFGF, FGF receptor-1 (FGFR-1) is expressed as early as embryonic day 8.5 (E8.5) to E9.5 in the rat telencephalon, with its expression being relatively confined to the proliferating neuroepithelium (Orr-Urtreger et al, 1991;Vaccarino et al, 1999a,b).…”

Loss of Glutamatergic Pyramidal Neurons in Frontal and Temporal Cortex Resulting from Attenuation of FGFR1 Signaling Is Associated with Spontaneous Hyperactivity in Mice

“…Some Fgf knock-out mice have provided insight into the biological roles of Fgfs in brain development. For example, Fgf2 knock-out mice have a loss of pyramidal neurons in the anterior cerebral cortex (Vaccarino et al, 1999;Korada et al, 2002), which is because of a deficiency in neural progenitorstem cells within the dorsal ventricular zone (VZ) (Vaccarino et al, 1999;Raballo et al, 2000). In contrast, the Fgf8 gene is required for cortical patterning, as shown by overexpression and conditional lack of function experiments (Meyers et al, 1998;Fukuchi-Shimogori and Grove, 2001;Garel et al, 2003).…”