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 genome-wide approaches.

Public Health Relevance

Genetic defects in human cerebral cortical development are tightly associated with intellectual disability, autism spectrum disorders and psychiatric disorders. Thus, besides greatly advancing our understanding on gene expression control of development of the cerebral cortex, our study will also provide crucial insights into the etiology of a wide range of neurodevelopmental disorders associated with intellectual disability and autism spectrum behaviors.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Riddle, Robert D
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Oregon Health and Science University
Schools of Medicine
United States
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Cargnin, Francesca; Kwon, Ji-Sun; Katzman, Sol et al. (2018) FOXG1 Orchestrates Neocortical Organization and Cortico-Cortical Connections. Neuron 100:1083-1096.e5