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.

Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies

“…Another described function of AKT is the regulation of the FOXG1 transcriptional repressor (Datta et al, 1999;Regad et al, 2007;Dastidar et al, 2011). FOXG1 plays crucial roles in early brain development, and loss of FOXG1 leads to microcephaly, developmental delay, and cerebral atrophy (Hettige and Ernst, 2019). Studies by Baek et al (2015) showed that expression of the Akt E17K variant by IUE altered AKT-FOXG1 signaling in mice, resulting in increased reelin expression during development.…”

Forkhead box R1-mediated stress response linked to a case of human microcephaly and brain atrophy

“…Mechanistically, FOXG1 interacts with the global transcriptional corepressors of the Groucho/transducing-like Enhancer of the split (TLE) family suggesting that FOXG1 acts as a transcriptional repressor coordinating the control of neural progenitor cell proliferation with the timing of differentiation (Yao et al , 2000). Disruption in FOXG1 in humans leads to structural brain abnormalities including microcephaly and agenesis of the corpus callosum (Shoichet et al , 2005; Kortum et al ., 2011; Hettige & Ernst, 2019). In addition, human mutations in both FOXP1 and FOXP2 lead to severe speech and cognitive impairments (Lai et al , 2000; MacDermot et al ., 2005; Takahashi et al , 2009; Horn et al , 2010; Nudel & Newbury, 2013; Han et al ., 2019); where both genes have also been linked to autism spectrum disorders (Takahashi et al ., 2009; Mukamel et al , 2011; Bowers & Konopka, 2012b, a).…”

“…Despite the high degree of conservation identity in the DNA-binding domain, Fox proteins bind different target sequences with great specificity, effecting regulation of the transcription of large array of genes directing major developmental processes such as cell proliferation and cell fate specification (Clark et al ., 1993; Carlsson & Mahlapuu, 2002; Lehmann et al , 2003; Nakagawa et al , 2013). Human genetic analyses have shown several FOX genes have important biological functions associated with brain development; these include FOXG1 (potential determinant of forebrain size; Florian et al , 2012; Hettige & Ernst, 2019; Pringsheim et al , 2019) and FOXP2 (vocal learning; MacDermot et al , 2005; Fisher & Scharff, 2009; Nudel & Newbury, 2013). Further, mutations in FOXG1, FOXC2, FOXL2, FOXP1 and FOXP2 have profound effects on human brain development including microcephaly, intellectual impairments, and language disorders (D’Haene et al , 2010; Kortum et al , 2011; Butler et al , 2012; Seltzer & Paciorkowski, 2014; Han et al , 2019).…”

The Role of FoxG1 in the Inner Ear

“…With the extension of development time, the expression area of FoxG1 changes. At mouse E12.5, FoxG1 is still expressed in the NPCs of the telencephalon, but no longer expressed in other neural tubes ( Hettige and Ernst, 2019 ). In the mature mouse brain, FoxG1 is only expressed in neuroepithelial cells such as the cerebral cortex and hippocampus ( Hettige and Ernst, 2019 ).…”

“…At mouse E12.5, FoxG1 is still expressed in the NPCs of the telencephalon, but no longer expressed in other neural tubes ( Hettige and Ernst, 2019 ). In the mature mouse brain, FoxG1 is only expressed in neuroepithelial cells such as the cerebral cortex and hippocampus ( Hettige and Ernst, 2019 ). These indicate that FoxG1 can regulate the telencephalic development through spatio-temporal patterning and interaction with different signaling.…”