Project description:How neurons are wired to form precise circuits is crucial to understand the development of cortical functions. Glutamatergic pyramidal cell and GABAergic interneuron wire up the cortex through differentiated cellular events. However, little is known about the molecular mechanisms that underlie the unique features of interneuron wiring. We performed a high-throughput genomic screen for genes upregulated specifically during GABAergic wiring.
Project description:Transcription factors (TFs) bind combinatorially to genomic cis-regulatory elements (cREs), orchestrating transcription programs. While studies of chromatin state and chromosomal interactions have revealed dynamic neurodevelopmental cRE landscapes, parallel understanding of the underlying TF binding lags. To elucidate the combinatorial TF-cRE interactions driving mouse basal ganglia development, we integrated ChIP-seq for twelve TFs, H3K4me3-associated enhancer-promoter interactions, chromatin and transcriptional state, and transgenic enhancer assays. We identified TF-cREs modules with distinct chromatin features and enhancer activity that have complementary roles driving GABAergic neurogenesis and suppressing other developmental fates. While the majority of distal cREs were bound by one or two TFs, a small proportion were extensively bound, and these enhancers also exhibited exceptional evolutionary conservation, motif density, and complex chromosomal interactions. Our results provide new insights into how modules of combinatorial TF-cRE interactions activate and repress developmental expression programs and demonstrate the value of TF binding data in modeling gene regulatory wiring.
Project description:During embryonic development, GABAergic interneurons, a main inhibitory component in the cerebral cortex, migrate tangentially from the ganglionic eminence (GE) to cerebral cortex. After reaching the cerebral cortex, they start to extend their neurites for constructing local neuronal circuits around the neonatal stage. Aberrations in migration or neurite outgrowth are implicated in neurological and psychiatric disorders such as epilepsy, schizophrenia and autism. Previous studies revealed that in the early phase of cortical development the neural population migrates tangentially from the GE in the telencephalon and several genes have been characterized as regulators of migration and specification of GABAergic interneurons. However, much less is known about the molecular mechanisms of GABAergic interneurons-specific maturation at later stages of development. Here, we performed genome-wide screening to identify genes related to the later stage by flow cytometry based-microarray (FACS-array) and identified 247 genes expressed in cortical GABAergic interneurons. Among them, Dgkg, a member of diacylglycerol kinase family, was further analyzed. Correlational analysis revealed that Dgkg is dominantly expressed in somatostatin (SST)-expressing GABAergic interneurons. The functional study of Dgkg using GE neurons indicated alteration in neurite outgrowth of GABAergic neurons. This study shows a new functional role for Dgkg in GABAergic interneurons as well as the identification of other candidate genes for their maturation.
Project description:RATIONALE: Identification of genes that may be associated with developing certain types of cancer may someday provide important information about a person’s risk of getting cancer.
PURPOSE: This clinical trial is studying to see if certain genes may be associated with cancer in patients with cancer of the breast, prostate, lung, or colon and siblings of these patients.