# FoxG1-directed Gene Network in Forebrain Development and FoxG1 Syndrome

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2021 · $492,948

## Abstract

Project Summary
The cerebral cortex is responsible for higher cognitive and emotional functions, and has served as an ideal
model to study CNS development due to enormous cellular complexity. Our long-term goal is to fully decode the
genetic and epigenetic mechanisms by which transcription factors (TFs) and chromatin remodelers cooperate
to regulate the cortex development and how disruption of such mechanisms leads to neurodevelopmental
disorders with impaired cortical functions. To address these two critical issues, here we propose to study the
role of the forkhead TF FoxG1 in corticogenesis and a human neurodevelopmental disorder FoxG1 syndrome
(FS) (aka, a congenital variant of Rett syndrome, RTT), which results from inactivating mutations in one allele
of the FoxG1 gene. Prominent clinical features of FS include microcephaly, agenesis of the corpus callosum,
profound intellectual disability with autistic features and absent language, and seizures. Duplication of FoxG1
is also associated with developmental epilepsy, intellectual disability, and severe speech and social impairment.
Overexpression of FoxG1 via unknown mechanism is also implicated in autism. These results indicate that
brain development is highly sensitive to the dosage of FoxG1.
 The mechanisms underlying timely neurogenesis and production of diverse cortical neuronal types are
beginning to be understood thanks to the discovery of TFs that are expressed with temporal and regional
specificity within the neocortex. During CNS development, the neurogenic TFs are often expressed in multiple
cell types, suggesting that neuronal TFs may acquire cell type-specific activity by regulating distinct sets of
target genes in cell context-dependent manner. However, the molecular mechanisms by which neuronal TFs
recognize and control cell type-specific transcription program in the developing cortex remain ill-defined.
FoxG1 is strongly expressed in forebrain NPCs, in which it regulates self-renewal and a timing of neurogenesis.
FoxG1 is downregulated during differentiation of NPCs, and then re-expressed in cortical neurons, in which
FoxG1 promotes neuronal entry into the cortical plate (CP). While these results suggest cell context-dependent
actions of FoxG1, the gene regulatory mechanisms by which FoxG1 controls the sequential steps of cortex
development and how these mechanisms relate to FS pathology are unclear. Our unbiased comprehensive
screening approaches (ChIPseq, RNAseq and proteomics) disclosed key clues for understanding the
molecular actions of FoxG1 in the developing cortex. Based on these seminal findings, we hypothesize that
FoxG1 regulates its target genes in a developmental timing sensitive manner by collaborating with cell type-
specific partner TFs and chromatin regulatory factors in cortex development, and dysregulation of these
processes leads to neurological deficits in FS. We will test this hypothesis using an ensemble of cellular,
biochemical, genetic, and comprehensive...

## Key facts

- **NIH application ID:** 10246537
- **Project number:** 5R01NS100471-05
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Soo-Kyung Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $492,948
- **Award type:** 5
- **Project period:** 2017-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246537

## Citation

> US National Institutes of Health, RePORTER application 10246537, FoxG1-directed Gene Network in Forebrain Development and FoxG1 Syndrome (5R01NS100471-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10246537. Licensed CC0.

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