Genetic Studies of Cortex Structure and Development

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PROJECT SUMMARY (30 lines) Dysregulation of cortical development is central to epilepsy, mental deficiency, autism and schizophrenia. Cortical progenitors generate the projection neurons of the cerebral cortex and hippocampus. Understanding the genetic circuitry controlling the development and function of the cortex is essential to interpret human allele variants in people who have neuropsychiatric disorders. To elucidate the genetic circuitry driving the development of cortical progenitors and neurons, we must define the essential transcription factors (TF), regulatory elements (REs) and coding regions. The proposed research on cortical regionalization and laminar specification, will overcome these barriers through the identification and functional characterization of REs implicated in cortical development. Further, the regulation of REs by chromatin modifiers is critical to their appropriate spatiotemporal activity8,9. Here we propose to make inroads into these subjects. We aim to elucidate transcriptional mechanisms through which patterning of cortical progenitors is transmitted to, and maintained in, cortical neurons. In this proposal, we will study TFs and their targets (putative REs or pREs) regulating cortical patterning and lamination (Aim 1). We will profile the regional and laminar epigenomic states of pREs using purified cortical progenitors and differentiating neurons (Aims 2 & 3). We will define the activity and function of pREs using transgenic mice and enhancer deletions (Aim 4). Finally, to define the function of chromatin modifiers in cortical regionalization and lamination, we will study a chromatin modifier conditional mutant (Kdm6b cKO, Aim 5). The proposed studies shift our research from the function of single genes towards understanding how transcriptional networks orchestrate cortical development. We will integrate, our collaborative large-scale genomics analyses of forebrain pREs1,43,44, with our ChIP-Seq (Chromatin Immunoprecipitation-Sequencing) analyses, to identify regional and laminar specific cortical pREs. This information can lead to insights about human disease alleles in non-coding sequences. Moreover, our results will provide critical information about the genetic control of cortical progenitors and neurons. Once integrated with human genetic information, this will lead to insights into how abnormalities in specific gene networks cause human neuropsychiatric disorders; insights that are essential for understanding etiology, diagnosis and perhaps treatment. For instance, mutations in Tbr1 increase autism risk40. Tbr1 encodes a TF that we discovered and functionally characterized2,3,13,38,41,42. We hypothesize that the work proposed herein will identify multiple novel putative REs (pREs), including for Tbr1, that control cortical development, and will be helpful to human geneticists to define the function of non-coding mutations that contribute to disease risk.