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Forkhead Box G1 ( ) 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. 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, 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 expression. In this review, we explore the emerging mechanisms of 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.

Foxg1 is one of the forkhead box genes that are involved in morphogenesis, cell fate determination, and proliferation, and Foxg1 was previously reported to be required for morphogenesis of the mammalian inner ear. However, Foxg1 knock-out mice die at birth, and thus the role of Foxg1 in regulating hair cell (HC) regeneration after birth remains unclear. Here we used Sox2 CreER/+ Foxg1 loxp/loxp mice and Lgr5-EGFP CreER/+ Foxg1 loxp/loxp mice to conditionally knock down Foxg1 specifically in Sox2+ SCs and Lgr5+ progenitors, respectively, in neonatal mice. We found that Foxg1 conditional knockdown (cKD) in Sox2+ SCs and Lgr5+ progenitors at postnatal day (P)1 both led to large numbers of extra HCs, especially extra inner HCs (IHCs) at P7, and these extra IHCs with normal hair bundles and synapses could survive at least to P30. The EdU assay failed to detect any EdU+ SCs, while the SC number was significantly decreased in Foxg1 cKD mice, and lineage tracing data showed that much more tdTomato+ HCs originated from Sox2+ SCs in Foxg1 cKD mice compared to the control mice. Moreover, the sphere-forming assay showed that Foxg1 cKD in Lgr5+ progenitors did not significantly change their sphere-forming ability. All these results suggest that Foxg1 cKD promotes HC regeneration and leads to large numbers of extra HCs probably by inducing direct trans-differentiation of SCs and progenitors to HCs. Real-time qPCR showed that cell cycle and Notch signaling pathways were significantly down-regulated in Foxg1 cKD mice cochlear SCs. Together, this study provides new evidence for the role of Foxg1 in regulating HC regeneration from SCs and progenitors in the neonatal mouse cochlea.

Objective Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders. Methods Caregivers of participants enrolled in the US Natural History Study of RTT and RTT-related disorders ( n  = 925) were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2 . Results The top caregiver concerns for classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The frequency of the top caregiver concerns for classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. Caregivers of participants with increased seizure severity often ranked seizures as the first concern, whereas caregivers of participants without active seizures often ranked hand use or communication as the top concern. Comparison across disorders found commonalities in the top caregiver concerns between classic RTT, atypical RTT, MECP2 duplication syndrome, CDKL5 deficiency disorder, and FOXG1 syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features. Conclusion The top caregiver concerns for individuals with RTT and RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers.

The study aimed at widening the clinical and genetic spectrum and assessing genotype–phenotype associations in FOXG1 syndrome due to FOXG1 variants. We compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher’s exact test and a nonparametric multivariate test. Among the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype–phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1. These data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.

The transcription factor Foxg1 is known to be continuously expressed at a high level in mature neurons in the telencephalon, but little is known about its role in neural plasticity. Mutations in human FOXG1 cause deficiencies in learning and memory and limit social ability, which is defined as FOXG1 syndrome, but its pathogenic mechanism remains unclear. To examine the role of Foxg1 in adults, we crossed Camk2a-Cre ER with Foxg1 fl/fl mice and conditionally disrupted Foxg1 with tamoxifen in mature neurons. We found that spatial learning and memory were significantly impaired when examined by the Morris water maze test. The cKO mice also showed a significant reduction in freezing time during the contextual and cued fear conditioning test, indicating that fear conditioning memory was affected. A remarkable reduction in Schaffer-collateral long-term potentiation was also recorded. Morphologically, the dendritic arborization and spine densities of hippocampal pyramidal neurons were significantly reduced. Primary cell culture further confirmed altered dendritic complexity after Foxg1 deletion. Our results indicated that Foxg1 plays an important role in maintaining the neural plasticity, which is vital to high-grade function.

An increasing body of research suggests that promoting microglial autophagy hinders the neuroinflammation initiated though the NLRP3 inflammasome activation in Alzheimer’s disease (AD). The function of FoxG1, a crucial transcription factor involved in cell survival by regulating mitochondrial function, remains unknown during the AD process and neuroinflammation occurs. In the present study, we firstly found that Aβ peptides induced AD-like neuroinflammation upregulation and downregulated the level of autophagy. Following low-dose Aβ25–35 stimulation, FoxG1 expression and autophagy exhibited a gradual increase. Nevertheless, with high-concentration Aβ25–35 treatment, progressive decrease in FoxG1 expression and autophagy levels as the concentration of Aβ25–35 escalated. In addition, FoxG1 has a positive effect on cell viability and autophagy in the nervous system. In parallel with the Aβ25–35 stimulation, we employed siRNA to decrease the expression of FoxG1 in N2A cells. A substantial reduction in autophagy level (Beclin1, LC3II, SQSTM1/P62) and a notable growth in inflammatory response (NLRP3, TNF-α, and IL-6) were observed. In addition, we found FoxG1 overexpression owned the effect on the activation of AMPK/mTOR autophagy pathway and siRNA-FoxG1 successfully abolished this effect. Lastly, FoxG1 suppressed the NLRP3 inflammasome and enhanced the cognitive function in AD-like mouse model induced by Aβ25–35. Confirmed by cellular and animal experiments, FoxG1 suppressed NLRP3-mediated neuroinflammation, which was strongly linked to autophagy regulated by AMPK/mTOR. Taken together, FoxG1 may be a critical node in the pathologic progression of AD and has the potential to serve as therapeutic target.

Cisplatin (CDDP) is a commonly used chemotherapeutic for osteosarcoma (OS) patients, and drug resistance remains as a major hurdle to undermine the treatment outcome. Here, we investigated the potential involvement of FoxG1 and BNIP3 in CDDP resistance of OS cells. FoxG1 and BNIP3 expression levels were detected in the CDDP‐sensitive and CDDP‐resistant OS tumors and cell lines. Mitophagy was observed through transmission electron microscope analysis. The sensitivity to CDDP in OS cells upon FoxG1 overexpression was examined in cell and animal models. We found that FoxG1 and BNIP3 showed significant downregulation in the CDDP‐resistant OS tumor samples and cell lines. CDDP‐resistant OS tumor specimens and cells displayed impaired mitophagy. FoxG1 overexpression promoted BNIP3 expression, enhanced mitophagy in CDDP‐resistant OS cells, and resensitized the resistant cells to CDDP treatment in vitro and in vivo. Our data highlighted the role of the FoxG1/BNIP3 axis in regulating mitophagy and dictating CDDP resistance in OS cells, suggesting targeting FoxG1/BNIP3‐dependent mitophagy as a potential strategy to overcome CDDP resistance in OS. Cisplatin (CDDP) resistance remains as a major hurdle to osteosarcoma treatment. Here, we uncovered the role of the FoxG1/BNIP3 axis in regulating mitophagy and dictating CDDP resistance in osteosarcoma cells, suggesting that targeting FoxG1/BNIP3‐dependent mitophagy could be a potential strategy to overcome CDDP resistance in osteosarcoma.

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.

Trigeminal Neuralgia (TN) is a debilitating disorder frequently accompanied by mood complications such as depression and anxiety. The current study sought to elucidate the molecular underpinnings that contribute to the pathogenesis of TN and its associated anxiety. Employing a partial transection of the infraorbital nerve (pT-ION) in a murine model, we successfully induced sustained primary and secondary orofacial allodynia alongside anxiety-like behavioral manifestations. Transcriptome-wide gene microarray analyses revealed a marked upregulation of Foxg1 subsequent to pT-ION. Targeted knockdown of Foxg1 , achieved through bilateral microinjection of adeno-associated virus harboring Foxg1-specific shRNA into the lateral habenula (LHb), resulted in a significant attenuation of both orofacial pain and anxiety-like behaviors. Subsequent RNA sequencing implicated Prkcd as a downstream effector gene modulated by Foxg1 . Pharmacological inhibition of protein kinase C delta, encoded by Prkcd , within the LHb markedly ameliorated pT-ION-induced symptomatology. The dual luciferase assay revealed that Foxg1 substantially enhances the transcriptional activity of the Prkcd gene. Collectively, these findings indicate that trigeminal nerve injury leads to Foxg1 upregulation in the LHb, which in turn elevates the expression of Prkcd , culminating in the manifestation of orofacial pain and anxiety-like behaviors. This work offers promising therapeutic targets and a conceptual framework for the clinical management of TN and its psychological comorbidities.

Cisplatin is widely used in clinical tumor chemotherapy but has severe ototoxic side effects, including tinnitus and hearing damage. This study aimed to determine the molecular mechanism underlying cisplatin-induced ototoxicity. In this study, we used CBA/CaJ mice to establish an ototoxicity model of cisplatin-induced hair cell loss, and our results showed that cisplatin treatment could reduce FOXG1 expression and autophagy levels. Additionally, H3K9me2 levels increased in cochlear hair cells after cisplatin administration. Reduced FOXG1 expression caused decreased microRNA (miRNA) expression and autophagy levels, leading to reactive oxygen species (ROS) accumulation and cochlear hair cell death. Inhibiting miRNA expression decreased the autophagy levels of OC-1 cells and significantly increased cellular ROS levels and the apoptosis ratio in vitro . In vitro , overexpression of FOXG1 and its target miRNAs could rescue the cisplatin-induced decrease in autophagy, thereby reducing apoptosis. BIX01294 is an inhibitor of G9a, the enzyme in charge of H3K9me2, and can reduce hair cell damage and rescue the hearing loss caused by cisplatin in vivo . This study demonstrates that FOXG1-related epigenetics plays a role in cisplatin-induced ototoxicity through the autophagy pathway, providing new ideas and intervention targets for treating ototoxicity.