Development of the central nervous system (CNS) depends on accurate spatiotemporal control of signaling pathways and transcriptional programs. Forkhead Box G1 (FOXG1) is one of the master regulators that play fundamental roles in forebrain development; from the timing of neurogenesis, to the patterning of the cerebral cortex. Mutations in the FOXG1 gene cause a rare neurodevelopmental disorder called FOXG1 syndrome, also known as congenital form of Rett syndrome. Patients presenting with FOXG1 syndrome manifest a spectrum of phenotypes, ranging from severe cognitive dysfunction and microcephaly to social withdrawal and communication deficits, with varying severities. To develop and improve therapeutic interventions, there has been considerable progress towards unravelling the multi-faceted functions of FOXG1 in the neurodevelopment and pathogenesis of FOXG1 syndrome. Moreover, recent advances in genome editing and stem cell technologies, as well as the increased yield of information from high throughput omics, have opened promising and important new avenues in FOXG1 research. In this review, we provide a summary of the clinical features and emerging molecular mechanisms underlying FOXG1 syndrome, and explore disease-modelling approaches in animals and human-based systems, to highlight the prospects of research and possible clinical interventions.

Type III interferons (IFNs) are the latest members of the IFN family. They play an important role in immune defense mechanisms, especially in antiviral responses at mucosal sites. Moreover, they control inflammatory reactions by modulating neutrophil and dendritic cell functions. Therefore, it is important to identify cellular mechanisms involved in the control of type III IFN expression. All IFN family members contain AU-rich elements (AREs) in the 3′-untranslated regions (3′-UTR) of their mRNAs that determine mRNA half-life and consequently the expressional level of these cytokines. mRNA stability is controlled by different proteins binding to these AREs leading to either stabilization or destabilization of the respective target mRNA. The KH-type splicing regulatory protein KSRP (also named KHSRP) is an important negative regulator of ARE-containing mRNAs. Here, we identify the interferon lambda 3 (IFNL3) mRNA as a new KSRP target by pull-down and immunoprecipitation experiments, as well as luciferase reporter gene assays. We characterize the KSRP-binding site in the IFNL3 3′-UTR and demonstrate that KSRP regulates the mRNA half-life of the IFNL3 transcript. In addition, we detect enhanced expression of IFNL3 mRNA in KSRP−/− mice, establishing a negative regulatory function of KSRP in type III IFN expression also in vivo. Besides KSRP the RNA-binding protein AUF1 (AU-rich element RNA-binding protein 1) also seems to be involved in the regulation of type III IFN mRNA expression.

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KH-type splicing regulatory protein (KSRP) is an RNA-binding protein that promotes mRNA decay and thereby negatively regulates cytokine expression at the post-transcriptional level. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated cytokine expression causing multiple organ manifestations; MRL-Faslpr mice are an established mouse model to study lupus disease pathogenesis. To investigate the impact of KSRP on lupus disease progression, we generated KSRP-deficient MRL-Faslpr mice (MRL-Faslpr/KSRP−/− mice). In line with the predicted role of KSRP as a negative regulator of cytokine expression, lupus nephritis was augmented in MRL-Faslpr/KSRP−/− mice. Increased infiltration of immune cells, especially of IFN-γ producing T cells and macrophages, driven by enhanced expression of T cell-attracting chemokines and adhesion molecules, seems to be responsible for worsened kidney morphology. Reduced expression of the anti-inflammatory interleukin-1 receptor antagonist may be another reason for severe inflammation. The increase of FoxP3+ T cells detected in the kidney seems unable to dampen the massive kidney inflammation. Interestingly, lymphadenopathy was reduced in MRL-Faslpr/KSRP−/− mice. Altogether, KSRP appears to have a complex role in immune regulation; however, it is clearly able to ameliorate lupus nephritis.

Forkhead box G1 (FOXG1) has important functions in neuronal differentiation and balances excitatory/inhibitory network activity. Thus far, molecular processes underlying FOXG1 function are largely unexplored. Here, we present a multiomics data set exploring how FOXG1 impacts neuronal maturation at the chromatin level in the mouse hippocampus. At a genome-wide level, FOXG1 i) both represses and activates transcription, ii) binds mainly to enhancer regions, iii) reconfigures the epigenetic landscape through bidirectional alteration of H3K27ac, H3K4me3, and chromatin accessibility, and iv) operates synergistically with NEUROD1. Interestingly, we could not detect a clear hierarchy of FOXG1 and NEUROD1, but instead, provide the evidence that they act in a highly cooperative manner to control neuronal maturation. Genes affected by the chromatin alterations impact synaptogenesis and axonogenesis. Inhibition of histone deacetylases partially rescues transcriptional alterations upon FOXG1 reduction. This integrated multiomics view of changes upon FOXG1 reduction reveals an unprecedented multimodality of FOXG1 functions converging on neuronal maturation. It fuels therapeutic options based on epigenetic drugs to alleviate, at least in part, neuronal dysfunction.