Abstract
Forkhead Box G1 (FOXG1) is a member of the Forkhead family of genes with non-redundant roles in brain development, where alteration of this gene’s expression significantly affects the formation and function of the mammalian cerebral cortex. FOXG1 haploinsufficiency in humans is associated with prominent differences in brain size and impaired intellectual development noticeable in early childhood, while homozygous mutations are typically fatal. As such, FOXG1 has been implicated in a wide spectrum of congenital brain disorders, including the congenital variant of Rett syndrome, infantile spasms, microcephaly, autism spectrum disorder (ASD) and schizophrenia. Recent technological advances have yielded greater insight into phenotypic variations observed in FOXG1 syndrome, molecular mechanisms underlying pathogenesis of the disease, and multifaceted roles of FOXG1 expression. In this review, we explore the emerging mechanisms of FOXG1 in a range of transcriptional to posttranscriptional events in order to evolve our current view of how a single transcription factor governs the assembly of an elaborate cortical circuit responsible for higher cognitive functions and neurological disorders.
Highlights
Forkhead Box G1 (FOXG1) is a winged-helix transcription factor that serves as a master regulator for brain development
In reflection of its functional importance, the non-redundant role of FOXG1 renders this gene highly vulnerable to subtle mutations introduced in its coding and non-coding sequences, which result in significant changes in brain size, circuit formation, sensorimotor processing, and cognitive behaviors
The knockdown of FOXG1, in turn, had the opposite effect. These results suggest that the shortening of the G2/M arrest via repression of CDKN1A and cyclin B1 primarily accounts for the accelerated cell cycle and proliferation in the presence of FOXG1 (Figure 1; Wang et al, 2018)
Summary
Forkhead Box G1 (FOXG1) is a winged-helix transcription factor that serves as a master regulator for brain development. Because the C-terminal domain is indispensable for antagonizing Transforming Growth Factor β (TGFβ)-pathway (Dou et al, 2000), these genetic and biochemical studies indicate vertebrate-conserved and mammalian-unique mechanisms of FOXG1 regulation through distinct structural domains, specially encoded in the N-terminus These and other observations lead further research unveiling the molecular origin underlying heterogeneity of FOXG1 symptoms at both the genetic and functional level. Motif analysis revealed other neural-development-associated transcription factor binding sites including the basic Helix-LoopHelix (bHLH), high mobility group (HMG) box, and CAAT box-binding Transcription Factor/Nuclear Factor-1 (CTF/NF1) factors, which are the key components of the neural stem cell transcriptional regulatory network (Mateo et al, 2015) These motifs were for example enriched in genes with methyltransferase function, and concordantly overexpression of FOXG1 affected key regulators of DNA methylation to facilitate dedifferentiation to neural stem cell-like properties (Bulstrode et al, 2017)
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