PLP1-Targeting Antisense Oligonucleotides Improve FOXG1 Syndrome Mice.

FOXG1 syndrome is a rare neurodevelopmental disorder of the telencephalon, for which there is no cure. Underlying heterozygous pathogenic variants in the Forkhead Box G1 (FOXG1) gene with resulting impaired or loss of FOXG1 function lead to severe neurological impairments. Here, we report a patient with a de novo pathogenic single nucleotide deletion c.946del (p.Leu316Cysfs*10) of the FOXG1 gene that causes a premature protein truncation. To study this variant in vivo, we generated and characterized Foxg1 c946del mice that recapitulate hallmarks of the human disorder. Accordingly, heterozygous Foxg1 c946del mice display neurological symptoms with aberrant neuronal networks and increased seizure susceptibility. Gene expression profiling identified increased oligodendrocyte- and myelination-related gene clusters. Specifically, we showed that expression of the c946del mutant and of other pathogenic FOXG1 variants correlated with overexpression of proteolipid protein 1 (Plp1), a gene linked to white matter disorders. Postnatal administration of Plp1-targeting antisense oligonucleotides (ASOs) in Foxg1 c946del mice improved neurological deficits. Our data suggest Plp1 as a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients.

Stephania tetrandra and Its Active Compound Coclaurine Sensitize NSCLC Cells to Cisplatin through EFHD2 Inhibition.

BACKGROUND: Adjuvant chemotherapy, particularly cisplatin, is recommended for non-small cell lung carcinoma (NSCLC) patients at high risk of recurrence. EF-hand domain-containing protein D2 (EFHD2) has been recently shown to increase cisplatin resistance and is significantly associated with recurrence in early-stage NSCLC patients. Natural products, commonly used as phytonutrients, are also recognized for their potential as pharmaceutical anticancer agents. RESULT: In this study, a range of Chinese herbs known for their antitumor or chemotherapy-enhancing properties were evaluated for their ability to inhibit EFHD2 expression in NSCLC cells. Among the herbs tested, Stephania tetrandra (S. tetrandra) exhibited the highest efficacy in inhibiting EFHD2 and sensitizing cells to cisplatin. Through LC-MS identification and functional assays, coclaurine was identified as a key molecule in S. tetrandra responsible for EFHD2 inhibition. Coclaurine not only downregulated EFHD2-related NOX4-ABCC1 signaling and enhanced cisplatin sensitivity, but also suppressed the stemness and metastatic properties of NSCLC cells. Mechanistically, coclaurine disrupted the interaction between the transcription factor FOXG1 and the EFHD2 promoter, leading to a reduction in EFHD2 transcription. Silencing FOXG1 further inhibited EFHD2 expression and sensitized NSCLC cells to cisplatin. CONCLUSIONS: S. tetrandra and its active compound coclaurine may serve as effective adjuvant therapies to improve cisplatin efficacy in the treatment of NSCLC.

OSBPL2 inhibition leads to apoptosis of cochlea hair cells in age-related hearing loss by inhibiting the AKT/FOXG1 signaling pathway.

Age-related hearing loss (AHL) is a prevalent and multifaceted condition that significantly impacts a substantial portion of the aging population. Oxysterol Binding Protein-like 2 (OSBPL2) has been identified as a causal gene for hearing loss. However, its role in AHL is still unclear. In this study, we investigated the effect of OSBPL2 on the survival of cochlea hair cells. To simulate AHL in vitro, hair cell-like inner ear cells (HEI-OC1) were exposed to H2O2 treatment. OSBPL2 expression was significantly increased in HEI-OC1 cells after H2O2 treatment. OSBPL2 knockdown augmented cell death and apoptosis in H2O2-induced HEI-OC1 cells. Besides, H2O2 treatment also led to the inactivation of the AKT and FOXG1 signaling pathways in HEI-OC1 cells. Mechanistically, OSBPL2 silencing reinforced the inactivation of the FOXG1 signaling pathway in H2O2-treated HEI-OC1 cells by inhibiting the AKT signaling pathway. Under H2O2 treatment, AKT inhibition by MK2206 augmented the apoptosis of HEI-OC1 cells; on the contrary, AKT activation by SC79 treatment partially rescued the apoptosis of OSBPL2-knockdown HEI-OC1 cells. In addition, FOXG1 silencing significantly reversed the effects of AKT activation on OSBPL2-knockdown HEI-OC1 cells. Moreover, OSBPL2 expression and the activation status of the AKT/FOXG1 signaling pathway were confirmed in the cochleae of young and old C57BL/6 mice. In conclusion, our study provides evidence that OSBPL2 inhibition sensitizes HEI-OC1 cells to H2O2-induced apoptosis via inactivation of the AKT/FOXG1 signaling pathway, suggesting that OSBPL2 acts as an important regulator in AHL.

foxg1a is required for hair cell development and regeneration in the zebrafish lateral line.

Mechanosensory hair cells located in the inner ear mediate the sensations of hearing and balance. If damaged, mammalian inner ear hair cells are unable to regenerate, resulting in permanent sensory deficits. Aquatic vertebrates like zebrafish (Danio rerio) have a specialized class of mechanosensory hair cells found in the lateral line system, allowing them to sense changes in water current. Unlike mammalian inner ear hair cells, lateral line hair cells can robustly regenerate following damage. In mammals, the transcription factor Foxg1 functions to promote normal development of the inner ear. Foxg1a is expressed in lateral line sensory organs in zebrafish larvae, but its function during lateral line development and regeneration has not been investigated. Our study demonstrates that mutation of foxg1a results in slower posterior lateral line primordium migration and delayed neuromast formation. In developing and regenerating neuromasts, we find that loss of Foxg1a function results in reduced hair cell numbers, as well as decreased proliferation of neuromast cells. Foxg1a specifically regulates the development and regeneration of Islet1-labeled hair cells. These data suggest that Foxg1 may be a valuable target for investigation of clinical hair cell regeneration.

miRNA-105-5p regulates the histone deacetylase HDAC2 through FOXG1 to affect the malignant biological behavior of triple-negative breast cancer cells.

BACKGROUND: Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer (BC). Some potential molecular targets have been identified, and miR-105-5p was found to be abnormally expressed in TNBC tissues. OBJECTIVE: The objective of this study was to probe the effect of miR-105-5p on TNBC via FOXG1/HDAC2-mediated acetylation. METHODS: An animal model of TNBC was established by injecting BC cells into the axillary area of nude mice. The levels of miR-105-5p, FOXG1, HDAC2, Bcl-2, Bax, and Ki67 were detected via RT‒qPCR, Western blotting and immunohistochemistry. Flow cytometry, CCK-8, Transwell and colony formation assays were used to measure apoptosis, proliferation and migration, respectively. Total histone acetylation levels were measured by ELISA. The binding of FOXG1 to HDAC2 was detected by co-immunoprecipitation. The binding relationship between miR-105-5p and FOXG1 was verified using a dual-luciferase reporter gene assay. RESULTS: In this study, miR-105-5p and HDAC2 were highly expressed in the MDA-MB-231 and BT-549 BC cell lines, whereas FOXG1 was expressed at low levels. The inhibition of miR-105-5p inhibited the proliferation and migration of MDA-MB-231 and BT-549 cells and promoted their apoptosis. Bioinformatics analysis revealed that miR-105-5p and FOXG1 had a negative targeting regulatory relationship. FOXG1 overexpression had a similar effect on cancer cells as the inhibition of miR-105-5p. Moreover, experiments revealed that FOXG1 and HDAC2 could bind to each other and that HDAC2 overexpression or treatment with the histone acetyltransferase inhibitor Garcinol weakened the effect of FOXG1 overexpression. In addition, FOXG1 knockdown inhibited the effect of the miR-105-5p inhibitor, while Garcinol treatment further enhanced the effect of FOXG1 knockdown, inhibited histone acetylation, promoted the proliferation and migration of cancer cells, and inhibited apoptosis. Moreover, the in vivo results confirmed the in vitro results. CONCLUSION: miR-105-5p promotes HDAC2 expression by reducing FOXG1, inhibits histone acetylation, and aggravates the malignant biological behavior of TNBC cells.

Foxg1 regulates translation of neocortical neuronal genes, including the main NMDA receptor subunit gene, Grin1.

BACKGROUND: Mainly known as a transcription factor patterning the rostral brain and governing its histogenesis, FOXG1 has been also detected outside the nucleus; however, biological meaning of that has been only partially clarified. RESULTS: Prompted by FOXG1 expression in cytoplasm of pallial neurons, we investigated its implication in translational control. We documented the impact of FOXG1 on ribosomal recruitment of Grin1-mRNA, encoding for the main subunit of NMDA receptor. Next, we showed that FOXG1 increases GRIN1 protein level by enhancing the translation of its mRNA, while not increasing its stability. Molecular mechanisms underlying this activity included FOXG1 interaction with EIF4E and, possibly, Grin1-mRNA. Besides, we found that, within murine neocortical cultures, de novo synthesis of GRIN1 undergoes a prominent and reversible, homeostatic regulation and FOXG1 is instrumental to that. Finally, by integrated analysis of multiple omic data, we inferred that FOXG1 is implicated in translational control of hundreds of neuronal genes, modulating ribosome engagement and progression. In a few selected cases, we experimentally verified such inference. CONCLUSIONS: These findings point to FOXG1 as a key effector, potentially crucial to multi-scale temporal tuning of neocortical pyramid activity, an issue with profound physiological and neuropathological implications.

Saikosaponin-d mediates FOXG1 to reverse docetaxel resistance in prostate cancer through oxidative phosphorylation.

BACKGROUND: Prostate cancer (PCa), a prevalent malignancy worldwide, is frequently identified in advanced stages due to the absence of distinctive early symptoms, thereby culminating in the development of chemotherapy-induced drug resistance. Exploring novel resistance mechanisms and identifying new therapeutic agents can facilitate the advancement of more efficacious strategies for PCa treatment. METHODS: Bioinformatics analysis was employed to investigate the expression of FOXG1 in PCa tissues. Subsequently, qRT-PCR was utilized to validate FOXG1 mRNA expression levels in corresponding PCa cell lines. FOXG1 knockdown was performed, and cell proliferation was assessed using CCK-8 assays, while cell migration and invasion capabilities were evaluated through wound healing and Transwell assays. Western blot and Seahorse analyzer were used to measure oxidative phosphorylation (OXPHOS) levels. Additionally, to explore potential approaches to alleviate PCa drug resistance, this study assessed the impact of biologically active saikosaponin-d (SSd) on PCa malignant progression and resistance by regulating FOXG1 expression. RESULTS: FOXG1 exhibited high expression in PCa tissues and cell lines. Knockdown of FOXG1 inhibited the proliferation, migration, and invasion of PCa cells, while FOXG1 overexpression had the opposite effect and promoted OXPHOS levels. The addition of an OXPHOS inhibitor prevented this outcome. Finally, SSd was shown to suppress FOXG1 expression and reverse docetaxel resistance in PCa cells through the OXPHOS pathway. CONCLUSION: This work demonstrated that SSd mediated FOXG1 to reverse malignant progression and docetaxel resistance in PCa through OXPHOS.

Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?

Rett syndrome (RTT) and Rett-like syndromes [i.e., CDKL5 deficiency disorder (CDD) and FOXG1-syndrome] represent rare yet profoundly impactful neurodevelopmental disorders (NDDs). The severity and complexity of symptoms associated with these disorders, including cognitive impairment, motor dysfunction, seizures and other neurological features significantly affect the quality of life of patients and families. Despite ongoing research efforts to identify potential therapeutic targets and develop novel treatments, current therapeutic options remain limited. Here the potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored. Leveraging existing drugs for new therapeutic purposes, DR presents an attractive strategy, particularly suited for neurological disorders given the complexities of the central nervous system (CNS) and the challenges in blood-brain barrier penetration. The current landscape of DR efforts in these syndromes is thoroughly examined, with partiuclar focus on shared molecular pathways and potential common drug targets across these conditions.

The postnatal injection of AAV9-FOXG1 rescues corpus callosum agenesis and other brain deficits in the mouse model of FOXG1 syndrome.

Heterozygous mutations in the FOXG1 gene manifest as FOXG1 syndrome, a severe neurodevelopmental disorder characterized by structural brain anomalies, including agenesis of the corpus callosum, hippocampal reduction, and myelination delays. Despite the well-defined genetic basis of FOXG1 syndrome, therapeutic interventions targeting the underlying cause of the disorder are nonexistent. In this study, we explore the therapeutic potential of adeno-associated virus 9 (AAV9)-mediated delivery of the FOXG1 gene. Remarkably, intracerebroventricular injection of AAV9-FOXG1 to Foxg1 heterozygous mouse model at the postnatal stage rescues a wide range of brain pathologies. This includes the amelioration of corpus callosum deficiencies, the restoration of dentate gyrus morphology in the hippocampus, the normalization of oligodendrocyte lineage cell numbers, and the rectification of myelination anomalies. Our findings highlight the efficacy of AAV9-based gene therapy as a viable treatment strategy for FOXG1 syndrome and potentially other neurodevelopmental disorders with similar brain malformations, asserting its therapeutic relevance in postnatal stages.

FoxG1/BNIP3 axis promotes mitophagy and blunts cisplatin resistance in osteosarcoma.

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.

Foxg1 bimodally tunes L1-mRNA and -DNA dynamics in the developing murine neocortex.

Foxg1 masters telencephalic development via a pleiotropic control over its progression. Expressed within the central nervous system (CNS), L1 retrotransposons are implicated in progression of its histogenesis and tuning of its genomic plasticity. Foxg1 represses gene transcription, and L1 elements share putative Foxg1-binding motifs, suggesting the former might limit telencephalic expression (and activity) of the latter. We tested such a prediction, in vivo as well as in engineered primary neural cultures, using loss- and gain-of-function approaches. We found that Foxg1-dependent, transcriptional L1 repression specifically occurs in neopallial neuronogenic progenitors and post-mitotic neurons, where it is supported by specific changes in the L1 epigenetic landscape. Unexpectedly, we discovered that Foxg1 physically interacts with L1-mRNA and positively regulates neonatal neopallium L1-DNA content, antagonizing the retrotranscription-suppressing activity exerted by Mov10 and Ddx39a helicases. To the best of our knowledge, Foxg1 represents the first CNS patterning gene acting as a bimodal retrotransposon modulator, limiting transcription of L1 elements and promoting their amplification, within a specific domain of the developing mouse brain.

Menin Deficiency Induces Autism-Like Behaviors by Regulating Foxg1 Transcription and Participates in Foxg1-Related Encephalopathy.

FOXG1 syndrome is a developmental encephalopathy caused by FOXG1 (Forkhead box G1) mutations, resulting in high phenotypic variability. However, the upstream transcriptional regulation of Foxg1 expression remains unclear. This report demonstrates that both deficiency and overexpression of Men1 (protein: menin, a pathogenic gene of MEN1 syndrome known as multiple endocrine neoplasia type 1) lead to autism-like behaviors, such as social defects, increased repetitive behaviors, and cognitive impairments. Multifaceted transcriptome analyses revealed that Foxg1 signaling is predominantly altered in Men1 deficiency mice, through its regulation of the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (Atrx) factor. Atrx recruits menin to bind to the transcriptional start region of Foxg1 and mediates the regulation of Foxg1 expression by H3K4me3 (Trimethylation of histone H3 lysine 4) modification. The deficits observed in menin deficient mice are rescued by the over-expression of Foxg1, leading to normalized spine growth and restoration of hippocampal synaptic plasticity. These findings suggest that menin may have a putative role in the maintenance of Foxg1 expression, highlighting menin signaling as a potential therapeutic target for Foxg1-related encephalopathy.

FoxG1 as a Potential Therapeutic Target for Alzheimer's Disease: Modulating NLRP3 Inflammasome via AMPK/mTOR Autophagy Pathway.

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 Aß peptides induced AD-like neuroinflammation upregulation and downregulated the level of autophagy. Following low-dose Aß25-35 stimulation, FoxG1 expression and autophagy exhibited a gradual increase. Nevertheless, with high-concentration Aß25-35 treatment, progressive decrease in FoxG1 expression and autophagy levels as the concentration of Aß25-35 escalated. In addition, FoxG1 has a positive effect on cell viability and autophagy in the nervous system. In parallel with the Aß25-35 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 Aß25-35. 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.

FOXG1 variants can be associated with milder phenotypes than congenital Rett syndrome with unassisted walking and language development.

Since 2008, FOXG1 haploinsufficiency has been linked to a severe neurodevelopmental phenotype resembling Rett syndrome but with earlier onset. Most patients are unable to sit, walk, or speak. For years, FOXG1 sequencing was only prescribed in such severe cases, limiting insight into the full clinical spectrum associated with this gene. Next-generation sequencing (NGS) now enables unbiased diagnostics. Through the European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders, we gathered data from patients with heterozygous FOXG1 variants presenting a mild phenotype, defined as able to speak and walk independently. We also reviewed data from three previously reported patients meeting our criteria. We identified five new patients with pathogenic FOXG1 missense variants, primarily in the forkhead domain, showing varying nonspecific intellectual disability and developmental delay. These features are not typical of congenital Rett syndrome and were rarely associated with microcephaly and epilepsy. Our findings are consistent with a previous genotype-phenotype analysis by Mitter et al. suggesting the delineation of five different FOXG1 genotype groups. Milder phenotypes were associated with missense variants in the forkhead domain. This information may facilitate prognostic assessments in children carrying a FOXG1 variant and improve the interpretation of new variants identified with genomic sequencing.

Evolutionarily conserved roles of foxg1a in the developing subpallium of zebrafish embryos.

The vertebrate telencephalic lobes consist of the pallium (dorsal) and subpallium (ventral). The subpallium gives rise to the basal ganglia, encompassing the pallidum and striatum. The development of this region is believed to depend on Foxg1/Foxg1a functions in both mice and zebrafish. This study aims to elucidate the genetic regulatory network controlled by foxg1a in subpallium development using zebrafish as a model. The expression gradient of foxg1a within the developing telencephalon was examined semi-quantitatively in initial investigations. Utilizing the CRISPR/Cas9 technique, we subsequently established a foxg1a mutant line and observed the resultant phenotypes. Morphological assessment revealed that foxg1a mutants exhibit a thin telencephalon together with a misshapen preoptic area (POA). Notably, accumulation of apoptotic cells was identified in this region. In mutants at 24 h postfertilization, the expression of pallium markers expanded ventrally, while that of subpallium markers was markedly suppressed. Concurrently, the expression of fgf8a, vax2, and six3b was shifted ventrally, causing anomalous expression in regions typical of POA formation in wild-type embryos. Consequently, the foxg1a mutation led to expansion of the pallium and disrupted the subpallium and POA. This highlights a pivotal role of foxg1a in directing the dorsoventral patterning of the telencephalon, particularly in subpallium differentiation, mirroring observations in mice. Additionally, reduced expression of neural progenitor maintenance genes was detected in mutants, suggesting the necessity of foxg1a in preserving neural progenitors. Collectively, these findings underscore evolutionarily conserved functions of foxg1 in the development of the subpallium in vertebrate embryos.

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy, intellectual disability, autistic features, speech deficits, and sleep and breathing abnormalities. Neurologically, patients with all three disorders display microcephaly, aberrant dendritic morphology, reduced spine density, and an imbalance of excitatory/inhibitory signaling. Loss-of-function mutations in the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1 genes also cause similar behavioral and neurobiological defects and were referred to as congenital or variant Rett syndrome. The relatively recent realization that CDKL5 deficiency disorder (CDD), FOXG1 syndrome, and Rett syndrome are distinct neurodevelopmental disorders with some distinctive features have resulted in separate focus being placed on each disorder with the assumption that distinct molecular mechanisms underlie their pathogenesis. However, given that many of the core symptoms and neurological features are shared, it is likely that the disorders share some critical molecular underpinnings. This review discusses the possibility that deregulation of common molecules in neurons and astrocytes plays a central role in key behavioral and neurological abnormalities in all three disorders. These include KCC2, a chloride transporter, vGlut1, a vesicular glutamate transporter, GluD1, an orphan-glutamate receptor subunit, and PSD-95, a postsynaptic scaffolding protein. We propose that reduced expression or activity of KCC2, vGlut1, PSD-95, and AKT, along with increased expression of GluD1, is involved in the excitatory/inhibitory that represents a key aspect in all three disorders. In addition, astrocyte-derived brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and inflammatory cytokines likely affect the expression and functioning of these molecules resulting in disease-associated abnormalities.

Foxg1 Modulation of the Prkcd Gene in the Lateral Habenula Mediates Trigeminal Neuralgia-Associated Anxiety-Like Behaviors in Mice.

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.

Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study.

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.

Conditional Deletion of Foxg1 Delayed Myelination during Early Postnatal Brain Development.

FOXG1 (forkhead box G1) syndrome is a neurodevelopmental disorder caused by variants in the Foxg1 gene that affect brain structure and function. Individuals affected by FOXG1 syndrome frequently exhibit delayed myelination in neuroimaging studies, which may impair the rapid conduction of nerve impulses. To date, the specific effects of FOXG1 on oligodendrocyte lineage progression and myelination during early postnatal development remain unclear. Here, we investigated the effects of Foxg1 deficiency on myelin development in the mouse brain by conditional deletion of Foxg1 in neural progenitors using NestinCreER;Foxg1fl/fl mice and tamoxifen induction at postnatal day 0 (P0). We found that Foxg1 deficiency resulted in a transient delay in myelination, evidenced by decreased myelin formation within the first two weeks after birth, but ultimately recovered to the control levels by P30. We also found that Foxg1 deletion prevented the timely attenuation of platelet-derived growth factor receptor alpha (PDGFRα) signaling and reduced the cell cycle exit of oligodendrocyte precursor cells (OPCs), leading to their excessive proliferation and delayed maturation. Additionally, Foxg1 deletion increased the expression of Hes5, a myelin formation inhibitor, as well as Olig2 and Sox10, two promoters of OPC differentiation. Our results reveal the important role of Foxg1 in myelin development and provide new clues for further exploring the pathological mechanisms of FOXG1 syndrome.