Patterning of frontal cortex subdivisions by Fgf17

Abstract

The frontal cortex (FC) is the seat of higher cognition. The genetic mechanisms that control formation of the functionally distinct subdivisions of the FC are unknown. Using a set of gene expression markers that distinguish subdivisions of the newborn mouse FC, we show that loss of Fgf17 selectively reduces the size of the dorsal FC whereas ventral/orbital FC appears normal. These changes are complemented by a rostral shift of sensory cortical areas. Thus, Fgf17 functions similar to Fgf8 in patterning the overall neocortical map but has a more selective role in regulating the properties of the dorsal but not ventral FC.arealization ͉ regionalization ͉ forebrain ͉ protomap ͉ neocortex T he frontal cortex (FC) consists of prefrontal, premotor, and motor areas that play a central role in cognition, movement, and behavior (1). The adult rodent prefrontal cortex (PFC) can be divided into medial and orbital regions that are thought to have homologues in primates (2). The medial PFC (mPFC) can be further subdivided into the dorsal mPFC, which includes frontal association, anterior cingulate, and dorsal prelimbic areas; and the ventral mPFC, which consists of ventral prelimbic, infralimbic, and medial orbital areas (3). The developmental mechanisms that generate FC subdivisions are unknown, in part, because of the lack of markers that distinguish these regions. In addition, most known mouse mutants that affect cortical patterning die at birth, precluding later analysis, when individual areas are distinguishable by classical histological methods.Current evidence shows that neocortical areas are presaged by regionalized expression of transcription factors and other regulatory genes in the cortical neuroepithelium and cortical plate, supporting the protomap model (4-7). Members of the fibroblast growth factor (Fgf ) family of genes have been implicated in controlling neocortical regionalization. Fgf8 and Fgf17 encode secreted signaling proteins and are expressed in a partially overlapping pattern in the rostral forebrain patterning center immediately adjacent to the developing FC [ Fig. 1A and supporting information (SI) Fig. 7] (8-11). Fgf8 patterns the neocortex in part by regulating the expression of transcription factor gradients in the cortical neuroepithelium (7,(12)(13)(14)(15)(16). Although ectopic expression of Fgf17 has been reported to have effects similar to that of Fgf8 in mediating overall patterning of the neocortical map (13), the role of endogenous Fgf17 in forebrain development is unknown.In this study we devised a panel of gene expression markers to examine the role of Fgf17 in the regionalization of the rodent FC using Fgf17-null mice (Fgf17 Ϫ/Ϫ ) (17). We report that the dorsal FC of Fgf17 Ϫ/Ϫ mice was reduced in size, whereas ventral and orbital FC regions appeared normal. The reduction in the dorsal FC area was complemented by a rostromedial shift of caudal cortical areas. These changes in regionalization persisted into adulthood and were accompanied by a reduction in FC projections to subcortical ta...

FGF8 acts as a classic diffusible morphogen to pattern the neocortex

“…9E, red lines, arrows), despite a significantly smaller overall neocortical area in the former (P<0.01). Fgf17 -/-, Fgf8 +/-;Fgf17 +/-and Fgf8 +/hy mice showed no significant differences with controls in overall neocortical area at this age (Cholfin and Rubenstein, 2007) (present study). These findings reveal functionally significant levels of both FGF8 and FGF17 in the posterior neocortical primordium that regulate regional specification and tissue growth.…”

“…The chief consequences of Fgf17 loss are in prefrontal cortex (Cholfin and Rubenstein, 2007), whereas, in mice hypomorphic for Fgf8, patterning shifts appear throughout neocortex (Garel et al, 2003). Nonetheless, the entire A/P extent of the neocortical primordium from E9.5 to E11.5 displays FGF17 IFl (see Fig.…”

“…Only FGF8 and FGF17 are implicated in area specification, however (Cholfin and Rubenstein, 2007;Cholfin and Rubenstein, 2008;FukuchiShimogori and Grove, 2001;Garel et al, 2003;Grove and Fukuchi-Shimogori, 2003), and because FGF17 has less influence on overall neocortical patterning than FGF8 (Cholfin and Rubenstein, 2007) (see below), most of the effect of dnFGFR3c on area identity is likely to be mediated by sequestering FGF8.…”

“…Decreased Fgf8/Fgf17 gene dose reduces FGF8/FGF17 protein activity (Cholfin and Rubenstein, 2007;Cholfin and Rubenstein, 2008), therefore, if FGF8 and FGF17 act together to pattern the entire neocortex, a progressive decrease in Fgf8/Fgf17 gene dose should generate progressive posterior to anterior boundary shifts in the area map. An analysis of neocortical area patterning in mice carrying Fgf17-null alleles (Xu et al, 1999;Xu et al, 2000), alone or in combination with null or hypomorphic (hy) alleles of Fgf8 (Moon and Capecchi, 2000) supported this hypothesis, and confirmed that FGF8 is the primary agent of the two in overall neocortical patterning.…”

“…FGF17 is required to specify dorsal prefrontal areas but does not have clear effects outside prefrontal cortex (Cholfin and Rubenstein, 2007;Cholfin and Rubenstein, 2008). FGF8, by contrast, has more widespread effects on the neocortical area map.…”