FGFR3 regulates brain size by controlling progenitor cell proliferation and apoptosis during embryonic development

Abstract

Mice with the K644E kinase domain mutation in fibroblast growth factor receptor 3 (Fgfr3) (EIIa;Fgfr3(+/K644E)) exhibited a marked enlargement of the brain. The brain size was increased as early as E11.5, not secondary to the possible effect of Fgfr3 activity in the skeleton. Furthermore, the mutant brains showed a dramatic increase in cortical thickness, a phenotype opposite to that in FGF2 knockout mice. Despite this increased thickness, cortical layer formation was largely unaffected and no cortical folding was observed during embryonic days 11.5-18.5 (E11.5-E18.5). Measurement of cortical thickness revealed an increase of 38.1% in the EIIa;Fgfr3(+/K644E) mice at E14.5 and the advanced appearance of the cortical plate was frequently observed at this stage. Unbiased stereological analysis revealed that the volume of the ventricular zone (VZ) was increased by more than two fold in the EIIa;Fgfr3(+/K644E) mutants at E14.5. A relatively mild increase in progenitor cell proliferation and a profound decrease in developmental apoptosis during E11.5-E14.5 most likely accounts for the dramatic increase in total telecephalic cell number. Taken together, our data suggest a novel function of Fgfr3 in controlling the development of the cortex, by regulating proliferation and apoptosis of cortical progenitors.

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.…”

Cell death in early neural life

“…This has been shown in mice with a gain-of-function mutation of FGFR3 (Inglis-Broadgate et al, 2005). The alternative possibility-a direct increase in neuroblasts without an effect on proliferating cell survival-has been observed in transgenic mice expressing a stabilized form of ␤-catenin (Chenn and Walsh, 2002).…”

Role of Intermediate Progenitor Cells in Cerebral Cortex Development

“…In humans, increased surface area and precocious formation of supernumerary gyri occur in thanatophoric dysplasia, a genetic disorder caused by activating mutations of fibroblast growth factor receptor 3 [53] . In a mouse model of thanatophoric dysplasia, the expansion of cortical surface area was linked to excessive proliferation of radial unit progenitors before E12.5 [54] .…”