Subpallial Enhancer Transgenic Lines: a Data and Tool Resource to Study Transcriptional Regulation of GABAergic Cell Fate.

Elucidating the transcriptional circuitry controlling forebrain development requires an understanding of enhancer activity and regulation. We generated stable transgenic mouse lines that express CreER and GFP from ten different enhancer elements with activity in distinct domains within the embryonic basal ganglia. We used these unique tools to generate a comprehensive regional fate map of the mouse subpallium, including sources for specific subtypes of amygdala neurons.

Migration of Founder Epithelial Cells Drives Proper Molar Tooth Positioning and Morphogenesis.

The proper positioning of organs during development is essential, yet little is known about the regulation of this process in mammals. Using murine tooth development as a model, we have found that cell migration plays a central role in positioning of the organ primordium. By combining lineage tracing, genetic cell ablation, and confocal live imaging, we identified a migratory population of Fgf8-expressing epithelial cells in the embryonic mandible.

Fgfr1 regulates development through the combinatorial use of signaling proteins.

Fibroblast growth factor (Fgf) signaling governs multiple processes important in development and disease. Many lines of evidence have implicated Erk1/2 signaling induced through Frs2 as the predominant effector pathway downstream from Fgf receptors (Fgfrs), but these receptors can also signal through other mechanisms. To explore the functional significance of the full range of signaling downstream from Fgfrs in mice, we engineered an allelic series of knock-in point mutations designed to disrupt Fgfr1 signaling functions individually and in combination.

OTX2 Transcription Factor Controls Regional Patterning within the Medial Ganglionic Eminence and Regional Identity of the Septum.

The Otx2 homeodomain transcription factor is essential for gastrulation and early neural development. We generated Otx2 conditional knockout (cKO) mice to investigate its roles in telencephalon development after neurulation (approximately embryonic day 9.0).

Fgf signaling controls the telencephalic distribution of Fgf-expressing progenitors generated in the rostral patterning center.

Background: The rostral patterning center (RPC) secretes multiple fibroblast growth factors (Fgfs) essential for telencephalon growth and patterning. Fgf expression patterns suggest that they mark functionally distinct RPC subdomains. We generated Fgf8(CreER) and Fgf17(CreER) mice and used them to analyze the lineages of Fgf8- versus Fgf17-expressing RPC cells.

Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6(+/-) mice.

Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (γ; ∼30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although γ rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia's typical post-adolescent onset also remain elusive.

Transcriptional regulation of enhancers active in protodomains of the developing cerebral cortex.

Elucidating the genetic control of cerebral cortical (pallial) development is essential for understanding function, evolution, and disorders of the brain. Transcription factors (TFs) that embryonically regulate pallial regionalization are expressed in gradients, raising the question of how discrete domains are generated. We provide evidence that small enhancer elements active in protodomains integrate broad transcriptional information.

A high-resolution enhancer atlas of the developing telencephalon.

The mammalian telencephalon plays critical roles in cognition, motor function, and emotion. Though many of the genes required for its development have been identified, the distant-acting regulatory sequences orchestrating their in vivo expression are mostly unknown. Here, we describe a digital atlas of in vivo enhancers active in subregions of the developing telencephalon.

Comparative mouse brain tractography of diffusion magnetic resonance imaging.

Diffusion magnetic resonance imaging (dMRI) tractography can be employed to simultaneously analyze three-dimensional white matter tracts in the brain. Numerous methods have been proposed to model diffusion-weighted magnetic resonance data for tractography, and we have explored the functionality of some of these for studying white and grey matter pathways in ex vivo mouse brain. Using various deterministic and probabilistic algorithms across a range of regions of interest we found that probabilistic tractography provides a more robust means of visualizing both white and grey matter pathways than deterministic tractography.

Genes and signaling events that establish regional patterning of the mammalian forebrain.

Embryonic development of the mammalian forebrain is guided by signals from four patterning centers. The concerted actions of these signals transform the anterior neural plate and prosencephalon into discrete forebrain structures including the telencephalon (cerebral cortex and basal ganglia) and hypothalamus. In this review, we describe the signaling, transcriptional, and regulatory events that lead to induction of the prospective telencephalon, and that instruct regional development of distinct telencephalic areas along the rostrocaudal and dorsoventral axes.

Context-specific requirements for Fgfr1 signaling through Frs2 and Frs3 during mouse development.

Fibroblast growth factor receptor 1 (Fgfr1) plays pleiotropic roles during embryonic development, but the mechanisms by which this receptor signals in vivo have not previously been elucidated. Biochemical studies have implicated Fgf receptor-specific substrates (Frs2, Frs3) as the principal mediators of Fgfr1 signal transduction to the MAPK and PI3K pathways. To determine the developmental requirements for Fgfr1-Frs signaling, we generated mice (Fgfr1(Delta)Frs/DeltaFrs) in which the Frs2/3-binding site on Fgfr1 is deleted.

Roles of PDGF in animal development.

Recent advances in genetic manipulation have greatly expanded our understanding of cellular responses to platelet-derived growth factors (PDGFs) during animal development. In addition to driving mesenchymal proliferation, PDGFs have been shown to direct the migration, differentiation and function of a variety of specialized mesenchymal and migratory cell types, both during development and in the adult animal. Furthermore, the availability of genomic sequence data has facilitated the identification of novel PDGF and PDGF receptor (PDGFR) family members in C.

An allelic series at the PDGFalphaR locus indicates unequal contributions of distinct signaling pathways during development.

A central issue in signal transduction is the physiological contribution of different growth factor-initiated signaling pathways. We have generated knockin mice harboring mutations in the PDGFalpha receptor (PDGFalphaR) that selectively eliminate its capacity to activate PI3 kinase (alpha(PI3K)) or Src family kinases (alpha(Src)). The alpha(PI3K) mutation leads to neonatal lethality due to impaired signaling in many cell types, but the alpha(Src) mutation only affects oligodendrocyte development.