Emergence of neuronal diversity from patterning of telencephalic progenitors.

During central nervous system (CNS) development, hundreds of distinct neuronal subtypes are generated from a single layer of multipotent neuroepithelial progenitor cells. Within the rostral CNS, initial regionalization of the telencephalon marks the territories where the cerebral cortex and the basal ganglia originate. Subsequent refinement of the primary structures determines the formation of domains of differential gene expression, where distinct fate-restricted progenitors are located. To understand how diversification of neural progenitors and neurons is achieved in the telencephalon, it is important to address early and late patterning events in this context. In particular, important questions include: How does the telencephalon become specified and regionalized along the major spatial axes? Within each region, are the differences in neuronal subtypes established at the progenitor level or at the postmitotic stage? If distinct progenitors exist that are committed to subtype-specific neuronal lineages, how does the diversification emerge? What is the contribution of positional and temporal cues and how is this information integrated into the intrinsic programs of cell identity? WIREs For further resources related to this article, please visit the WIREs website.This work was supported by Medical Research Council (MRC) grants G0700758 and MR/K018329/1 and Doctoral Training Award (LH); RA is supported by an MRC postdoctoral fellowship.This is the accepted manuscript. The final version is available from Wiley at http://onlinelibrary.wiley.com/doi/10.1002/wdev.174/abstract

FGF-2 Deficiency Does Not Influence FGF Ligand and Receptor Expression during Development of the Nigrostriatal System

Secreted proteins of the fibroblast growth factor (FGF) family play important roles during development of various organ systems. A detailed knowledge of their temporal and spatial expression profiles, especially of closely related FGF family members, are essential to further identification of specific functions in distinct tissues. In the central nervous system dopaminergic neurons of the substantia nigra and their axonal projections into the striatum progressively degenerate in Parkinson's disease. In contrast, FGF-2 deficient mice display increased numbers of dopaminergic neurons. In this study, we determined the expression profiles of all 22 FGF-ligands and 10 FGF-receptor isoforms, in order to clarify, if FGF-2 deficiency leads to compensatory up-regulation of other FGFs in the nigrostriatal system. Three tissues, ventral mesencephalon (VM), striatum (STR) and as reference tissue spinal cord (SC) of wild-type and FGF-2 deficient mice at four developmental stages E14.5, P0, P28, and adult were comparatively analyzed by quantitative RT-PCR. As no differences between the genotypes were observed, a compensatory up-regulation can be excluded. Moreover, this analysis revealed that the majority of FGF-ligands (18/22) and FGF-receptors (9/10) are expressed during normal development of the nigrostriatal system and identified dynamic changes for some family members. By comparing relative expression level changes to SC reference tissue, general alterations in all 3 tissues, such as increased expression of FGF-1, -2, -22, FgfR-2c, -3c and decreased expression of FGF-13 during postnatal development were identified. Further, specific changes affecting only one tissue, such as increased FGF-16 (STR) or decreased FGF-17 (VM) expression, or two tissues, such as decreased expression of FGF-8 (VM, STR) and FGF-15 (SC, VM) were found. Moreover, 3 developmentally down-regulated FGFs (FGF-8b, FGF-15, FGF-17a) were functionally characterized by plasmid-based over-expression in dissociated E11.5 VM cell cultures, however, such a continuous exposure had no influence on the yield of dopaminergic neurons in vitro

A Novel Role for Dbx1-Derived Cajal-Retzius Cells in Early Regionalization of the Cerebral Cortical Neuroepithelium

Patterning of the cerebral cortex during embryogenesis depends not only on passive diffusion of morphogens but also on signal delivery by Cajal-Retzius neurons that migrate over long distances

Segment-Specific Neuronal Subtype Specification by the Integration of Anteroposterior and Temporal Cues

To address the question of how neuronal diversity is achieved throughout the CNS, this study provides evidence of modulation of neural progenitor cell “output” along the body axis by integration of local anteroposterior and temporal cues

Genetic regulation of prefrontal cortex development

The prefrontal cortex (PFC) has been called "the organ of civilization" (Luria). The most anterior part of cerebral cortex, the PFC consists of multiple areas that mediate a wide range of higher-order behaviors 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) signaling from the rostral patterning center could have a central role in regulating rostral telencephalic development. A subset of FGF genes are expressed in the rostral patterning center in the embryonic telencephalon. Recent evidence shows that FGFs regulate the graded expression of regulatory genes (i.e. Emx2) in the cortical neuroepithelium, which may specify the initial distribution of PFC regional subdivisions and ultimately mature areas. I have devised a novel panel of gene expression markers to study the roles of Fgf17 and Fgf8, and genetic interactions between Fgf17 and Emx2 in patterning the frontal cortex. In addition, I have identified signaling mechanisms and genetic interactions during early forebrain development that may contribute to the postnatal regionalization phenotypes. Finally, I have initiated behavioral studies through collaborations with other laboratories to investigate higher-order behaviors that are dependent on intact PFC function. I have found that Fgf17, Fgf8 and Emx2 each play unique roles in the early regionalization of the PFC, and that Fgf17 and Emx2 specifically interact on the genetic level to regulate this process. In addition, Fgf17 mutant mice exhibit circumscribed deficits in social behavior and associated selective hypo-activation of the dorsal PFC. These studies reveal that the organization of subdivisions within a higher-order cortical area is partially under genetic control, and suggest that mispatterning of the PFC via genetic mutation may contribute to abnormal behavior

Genetic regulation of prefrontal cortex development

The prefrontal cortex (PFC) has been called "the organ of civilization" (Luria). The most anterior part of cerebral cortex, the PFC consists of multiple areas that mediate a wide range of higher-order behaviors 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) signaling from the rostral patterning center could have a central role in regulating rostral telencephalic development. A subset of FGF genes are expressed in the rostral patterning center in the embryonic telencephalon. Recent evidence shows that FGFs regulate the graded expression of regulatory genes (i.e. Emx2) in the cortical neuroepithelium, which may specify the initial distribution of PFC regional subdivisions and ultimately mature areas. I have devised a novel panel of gene expression markers to study the roles of Fgf17 and Fgf8, and genetic interactions between Fgf17 and Emx2 in patterning the frontal cortex. In addition, I have identified signaling mechanisms and genetic interactions during early forebrain development that may contribute to the postnatal regionalization phenotypes. Finally, I have initiated behavioral studies through collaborations with other laboratories to investigate higher-order behaviors that are dependent on intact PFC function. I have found that Fgf17, Fgf8 and Emx2 each play unique roles in the early regionalization of the PFC, and that Fgf17 and Emx2 specifically interact on the genetic level to regulate this process. In addition, Fgf17 mutant mice exhibit circumscribed deficits in social behavior and associated selective hypo-activation of the dorsal PFC. These studies reveal that the organization of subdivisions within a higher-order cortical area is partially under genetic control, and suggest that mispatterning of the PFC via genetic mutation may contribute to abnormal behavior