FOXG1 Dose in Brain Development

Abstract

Brain development is a highly regulated process that involves the precise spatio-temporal activation of cell signaling cues. Transcription factors play an integral role in this process by relaying information from external signaling cues to the genome. The transcription factor Forkhead box G1 (FOXG1) is expressed in the developing nervous system with a critical role in forebrain development. Altered dosage of FOXG1 due to deletions, duplications, or functional gain- or loss-of-function mutations, leads to a complex array of cellular effects with important consequences for human disease including neurodevelopmental disorders. Here, we review studies in multiple species and cell models where FOXG1 dose is altered. We argue against a linear, symmetrical relationship between FOXG1 dosage states, although FOXG1 levels at the right time and place need to be carefully regulated. Neurodevelopmental disease states caused by mutations in FOXG1 may therefore be regulated through different mechanisms.

Keywords: BF-1; FOXG1; gene dosage; iPSCs; neural stem cell; neurodevelopment.

Figure 1

FOXG1 dosage in neurodevelopment. FOXG1 expression levels are currently unknown; however, FOXG1 is one of the earliest genes to be expressed in mammalian telencephalon. We envision FOXG1 expression being activated well before terminal differentiation of forebrain neurons and even forebrain neural progenitors. Here, we depict expression patterns from a stem cell state to forebrain neurons, with induction and maintenance states defined. Circular plates show the appearance of cells in vitro for the different cell states. We model FOXG1 dosage changes as linear with respect to gene dosage, even though the molecular effects of FOXG1 protein (e.g., interaction with different proteins or different genomic regions) are not necessarily linear with respect to protein dose.