Transcription and Beyond: Delineating FOXG1 Function in Cortical Development and Disorders

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.

Keywords: FOXG1; FOXG1 syndrome; cellular reprogramming; cortical development; cortical organoid; posttranscriptional regulation; transcription factor.

Figure 1

Roles of Forkhead Box G1 (FOXG1) in progenitor cell maintenance and suppression of differentiation. To prevent cell cycle exit, FOXG1 cooperates with Groucho/Transducin-like Enhancer of split (TLE) proteins to inhibit key cell cycle protein expression. FOXG1 also inhibits differentiation gene and DNA/Histone modifiers to prevent neuronal differentiation.

Figure 2

FOXG1 directs multiple laminar fate decisions in the cerebral cortex. During corticogenesis, cortical neurons are sequentially produced, migrate and integrate into the destined layers. In this process, the onset of FOXG1 in the progenitor cells suppresses the production of L1/6 TBR1-expressing neurons and switches to L5 FEZF2/CTIP2-expressing neuron production. Later in early postmitotic neurons, FOXG1 inhibits COUP-TFI to switch the neuronal production from L4 Related Orphan Receptor B (RORβ)—to L2/3 SATB2/BRN2—expressing neurons.

Figure 3

FOXG1 functions outside the nucleus. In the cytosol, FOXG1 cooperates with DDX5 and microprocessors to induce miR-200 biogenesis and promote postsynaptic function. In the mitochondrial membrane, FOXG1 controls mitochondrial mitosis and its expression in the matrix regulates early neuronal differentiation.