ABSTRACT
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 Fgf8(neo/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.
Subject(s)
Fibroblast Growth Factor 8/physiology , Fibroblast Growth Factors/physiology , Frontal Lobe/physiology , Gene Expression Regulation, Developmental/physiology , Homeodomain Proteins/physiology , Nerve Tissue Proteins/physiology , Transcription Factors/physiology , Amino Acid Sequence , Animals , Animals, Newborn , Fibroblast Growth Factor 8/deficiency , Fibroblast Growth Factor 8/genetics , Fibroblast Growth Factors/deficiency , Fibroblast Growth Factors/genetics , Forkhead Transcription Factors/biosynthesis , Forkhead Transcription Factors/genetics , Frontal Lobe/anatomy & histology , Frontal Lobe/embryology , Frontal Lobe/growth & development , Homeodomain Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Neurological , Molecular Sequence Data , Morphogenesis/genetics , Morphogenesis/physiology , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Neuroepithelial Cells/metabolism , Organ Specificity , Signal Transduction/genetics , Signal Transduction/physiology , Transcription Factors/biosynthesis , Transcription Factors/deficiency , Transcription Factors/genetics , Transcription, GeneticABSTRACT
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.
Subject(s)
Body Patterning , Fibroblast Growth Factors/metabolism , Frontal Lobe/embryology , Animals , Biomarkers , Fibroblast Growth Factor 8/metabolism , Fibroblast Growth Factors/deficiency , Fibroblast Growth Factors/genetics , Frontal Lobe/metabolism , Gene Expression Regulation, Developmental , Mice , Mice, Knockout , Mutation/geneticsABSTRACT
The prefrontal cortex (PFC) consists of multiple areas that mediate a wide range of higher-order behaviours in mammals. Despite years of intensive neuroanatomical and functional studies, little is known about the genetic mechanisms that pattern this structure during development. It has been recognized that fibroblast growth factor (FGF) signalling from the rostral patterning centre could have a central role in regulating rostral telencephalic development. A subset of FGF genes are expressed in the rostral patterning centre in the embryonic telencephalon. Recent evidence shows that FGFs, including Fgf17, regulate the graded expression of regulatory genes in the cortical neuroepithelium, which may specify the initial distribution of PFC regional subdivisions and ultimately mature areas.
Subject(s)
Gene Expression Regulation, Developmental , Prefrontal Cortex/embryology , Prefrontal Cortex/physiology , Animals , Body Patterning/genetics , Fibroblast Growth Factors/physiology , Humans , Signal Transduction/physiologyABSTRACT
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.
