# Genetic Studies of Cortex Structure and Development

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $605,465

## Abstract

PROJECT SUMMARY
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 informa...

## Key facts

- **NIH application ID:** 9976603
- **Project number:** 5R01NS099099-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JOHN L. R. RUBENSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $605,465
- **Award type:** 5
- **Project period:** 2016-09-30 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976603

## Citation

> US National Institutes of Health, RePORTER application 9976603, Genetic Studies of Cortex Structure and Development (5R01NS099099-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9976603. Licensed CC0.

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