In the adult brain, neuroblasts born in the subventricular zone migrate from the walls of the lateral ventricles to the olfactory bulb. How do these cells orient over such a long distance and through complex territories? Here we show that neuroblast migration parallels cerebrospinal fluid (CSF) flow. Beating of ependymal cilia is required for normal CSF flow, concentration gradient formation of CSF guidance molecules, and directional migration of neuroblasts. Results suggest that polarized epithelial cells contribute important vectorial information for guidance of young, migrating neurons.

The frontal cortex (FC) plays a major role in cognition, movement and behavior. However, little is known about the genetic mechanisms that govern its development. We recently described a panel of gene expression markers that delineate neonatal FC subdivisions and identified FC regionalization defects in Fgf17−/− mutant mice (Cholfin and Rubenstein [2007] Proc. Natl. Acad. Sci. U. S. A. [in press]). In the present study, we applied this FC gene expression panel to examine regionalization phenotypes in Fgf8neo/neo, Emx2−/−, and Emx2−/−; Fgf17−/− newborn mice. We report that Fgf8, Fgf17 and Emx2 play distinct roles in the molecular regionalization of FC subdivisions. The changes in regionalization are presaged by differential effects of rostral patterning center Fgf8 and Fgf17 signaling on the rostral cortical neuroepithelium, revealed by altered expression of Spry1, Spry2, and “rostral” transcription factors Er81, Erm, Pea3, and Sp8. We used Emx2−/−; Fgf17−/− double mutants to provide direct evidence that Emx2 and Fgf17 antagonistically regulate the expression of Erm, Pea3, and Er81 in the rostral cortical neuroepithelium and FC regionalization. We have integrated our results to propose a model for how fibroblast growth factors regulate FC patterning through regulation of regional transcription factor expression within the FC anlage.

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...

The fibroblast growth factor family of secreted signaling molecules is essential for patterning in the central nervous system. Fibroblast growth factor 17 (Fgf17) has been shown to contribute to regionalization of the rodent frontal cortex. To determine how Fgf17 signaling modulates behavior, both during development and in adulthood, we studied mice lacking one or two copies of the Fgf17 gene. Fgf17-deficient mice showed no abnormalities in overall physical growth, activity level, exploration, anxiety-like behaviors, motor co-ordination, motor learning, acoustic startle, prepulse inhibition, feeding, fear conditioning, aggression and olfactory exploration. However, they displayed striking deficits in several behaviors involving specific social interactions. Fgf17-deficient pups vocalized less than wild-type controls when separated from their mother and siblings. Elimination of Fgf17 also decreased the interaction of adult males with a novel ovariectomized female in a social recognition test and reduced the amount of time opposite-sex pairs spent engaged in prolonged, affiliative interactions during exploration of a novel environment. After social exploration of a novel environment, Fgf17-deficient mice showed less activation of the immediateearly gene Fos in the frontal cortex than wild-type controls. Our findings show that Fgf17 is required for several complex social behaviors and suggest that disturbances in Fgf17 signaling may contribute to neuropsychiatric diseases that affect such behaviors.