Dysregulation of the cerebral cortex is central to human developmental disorders such as epilepsy, mental deficiency, autism and schizophrenia. During development, cortical progenitors generate the projection neurons of the different cortical subdivisions. Understanding the genetic circuitry controlling the development and function of these neurons provides an essential foundation for interpreting human allele variants that are enriched in people who have neuropsychiatric disorders. To elucidate this genetic circuitry, we must define the transcription factors (TF), and regulatory elements and of the coding regions that they control. The proposed research, which concentrates on cortical regionalization, involves the systematic identification of TFs, and the regulatory elements and genes downstream of TFs. Currently, the regional-specification functions of a few TFs in embryonic cortical progenitors are known, and little is known about their direct transcription targets, the nature of the regulatory elements that these TFs control, and the transcriptional circuitry that integrates development and function of these cells. Here we propose to make inroads into each of these components of the TF hierarchy regulating cortical development. Furthermore, we aim to elucidate transcriptional mechanisms through which patterning of cortical progenitors is transmitted to, and maintained in, cortical neurons. We hypothesize that enhancers active in the ventricular zone, subventricular zone and the cortical plate are differentially bound by TFs that drive expression of region/layer-specific genes in post-mitotic cortical neurons. The enhancers serve as protein-binding modules that translate rostrocaudal gradients of TFs in cortical progenitors into region-specific expression in cortical neurons. Herein we focus on the transcriptional mechanisms controlling the generation of different regions of the cerebral cortex (cortical regionalization). The Five Specific Aims extend upon our earlier work on regionalization of cortical progenitors by FGF-signaling, TFs and enhancer elements. Here we investigate transcriptional regulation of cortical patterning by defining the TFs, and other genes, that are regulated by COUPTF1, EMX2, and PAX6 (Aim 1). We then use chromatin immunoprecipitation-DNA sequencing (ChIP-Seq) to define the regulatory element (RE) and gene targets of COUPTF1, EMX2, and PAX6 (Aim 2). Next, we use fluorescent activated cell sorting (FACS) to purify cells from the VZ, SVZ, CP and layers 5&6 to elucidate the epigenomic states of REs (and genes) using Histone ChIP-Seq. This will help us understand the molecular mechanisms that transmit regional patterning information from cortical progenitors to neurons (Aim 3). Finally, we define the function of REs related to cortical patterning using transgenic mice to assess RE activity (Aims 4) and REs deletions to define their role in gene regulation (Aim 5). Once integrated with human genetic information, this will enable us to gain powerful insights into how abnormalities in specific gene networks cause human neuropsychiatric disorders.

Public Health Relevance

Disruption of cerebral cortex development and function is strongly associated with several major neuropsychiatric disorders, including mental retardation, epilepsy, cerebral palsy, autism and schizophrenia. The experiments proposed in this application aim to elucidate basic mechanisms that underlie normal development of cerebral cortex. This information will provide a key foundation for understanding the genetic and molecular mechanisms underlying many neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS099099-01
Application #
9214258
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
2016-09-30
Project End
2021-06-30
Budget Start
2016-09-30
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$643,695
Indirect Cost
$237,578
Name
University of California San Francisco
Department
Psychiatry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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