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Glioblastoma (GBM) is the most common and deadly malignant brain cancer of glial cell origin, with a median patient survival of less than 20 months. Transcription factors FOXG1 and TLE1 promote GBM propagation by supporting maintenance of brain tumour‐initiating cells (BTICs) with stem‐like properties. Here, we characterize FOXG1 and TLE1 target genes in GBM patient‐derived BTICs using ChIP‐Seq and RNA‐Seq approaches. These studies identify 150 direct FOXG1 targets, several of which are also TLE1 targets, involved in cell proliferation, differentiation, survival, chemotaxis and angiogenesis. Negative regulators of NOTCH signalling, including CHAC1, are among the transcriptional repression targets of FOXG1:TLE1 complexes, suggesting a crosstalk between FOXG1:TLE1 and NOTCH‐mediated pathways in GBM. These results provide previously unavailable insight into the transcriptional programs underlying the tumour‐promoting functions of FOXG1:TLE1 in GBM. [ABSTRACT FROM AUTHOR]

FOXG1 -related syndrome is a developmental encephalopathy with a high phenotypic variability. A movement disorder presenting at onset is one of the main features, along with microcephaly and severe psychomotor delay without regression. Specific brain MRI findings facilitate the diagnosis. We report three cases of FOXG1 -related syndrome, focusing on clinical onset, brain MRI and evolution over time in order to identify common features despite the three different underlying genotypes (14q12 deletion including the FOXG1 gene, FOXG1 intragenic mutation, 14q12 deletion including PRKD1 and a region regulating FOXG1 expression). In conclusion, we stress the importance of considering genetic syndromes in the differential diagnosis of early-onset movement disorders. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To identify the functioning mode of miR-378 on non-small cell lung cancer (NSCLC) and provide therapeutic targets for NSCLC. PATIENTS AND METHODS: Expression levels of miR-378 in human NSCLC tissue samples and NSCLC-derived cell lines were measured by using quantitative Real-time polymerase chain reaction (PCR). Cell proliferation capacity was assessed by methyl thiazolyl tetrazolium (MTT) assay and colony formation assay. Cell apoptosis and cell cycle distribution were identified by flow cytometry. Downstream target gene was confirmed by using luciferase and Western blotting assays. RESULTS: MiR-378 was significantly elevated in NSCLC tissues when compared with para-carcinoma tissues (n=42). Decreased-miR-378 could attenuate cell proliferation capacity, as well as promoted cell apoptosis and induced cell cycle arrest at G0/G1 phase. FOXG1 was chosen as the target gene of miR-378 by bioinformatics analysis and luciferase reporter assay. Moreover, restoration of miR-378 could impair the tumor suppression role of downregulated-miR-378 on NSCLC growth. CONCLUSIONS: Decreased-miR-378 exerted tumor-suppressive effects on NSCLC growth via targeting FOXG1 in vitro, which provided an innovative and candidate target for diagnosis and treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Foxg1 is a transcription factor critical for the development of the mammalian telencephalon. Foxg1 controls the proliferation of dorsal telencephalon progenitors and the specification of the ventral telencephalon. Homozygous knockout of Foxg1 in mice leads to severe microcephaly, attributed to premature differentiation of telencephalic progenitors, mainly of cortical progenitors. Here, we analyzed the influence of a Foxg1 knockout on differentiation of murine pluripotent stem cells (mPSCs) in an in vitro model of neuronal development. Murine PSCs were prone to neuronal differentiation in embryoid body like culture with minimal medium conditions, based on the intrinsic default of PSCs to develop into cortical progenitors. Differences between Foxg1 wildtype (Foxg1 WT ) and knockout (Foxg1 KO ) mPSCs were analyzed. Several mPSC lines with homozygous mutations in Foxg1 were produced using the CRISPR/Cas9 system leading to loss of functional domains. Analysis of mRNA expression using quantitative Real-Time (q) PCR revealed that Foxg1 KO mPSCs expressed significantly less mRNA of Foxg1, Emx1, and VGlut1 compared to Foxg1 WT controls, indicating reduced differentiation towards dorsal telencephalic progenitors. However, the size of the derived EB-like structures did not differ between Foxg1 WT and Foxg1 KO mPSCs. These results show that loss of dorsal telencephalic progenitors can be detected using a simple and rapid differentiation protocol. This study is a first hint that this differentiation method can be used to analyze even extreme phenotypes that are lethal in vivo . [ABSTRACT FROM AUTHOR]

Abstract: The FOXG1 syndrome is emerging as a relative new entity in paediatric neurology. We report a boy with acquired microcephaly, mental retardation and a thin genu of the corpus callosum. The combination of these findings led to mutation analysis of FOXG1. The patient was found to be heterozygous for a novel mutation in FOXG1, c.506dup (p.Lys170GInfsX285), which occurred de novo. This frameshift mutation disturbs the three functional domains of the FOXG1 gene. Hypo- or agenesis of the anterior corpus callosum in combination with acquired microcephaly and neurologic impairment can be an important clue for identifying patients with a mutation in FOXG1. [Copyright &y& Elsevier]

Summary: Bacterial artificial chromosome array comparative genomic hybridization analysis of hepatoblastomas reveals a deletion in the 14q12 locus in 12 of 16 cases. A high frequency of copy gain is seen on chromosomes 1q, 2, 5p, 8, and 20. Frequent deletions are also seen at 6q, 17q, and 1p with less frequent gains on 4p, 6p, and 19p. 14q12 deletion locus analyses using quantitative real-time polymerase chain reaction reveals copy number gain/amplification in the region immediately telomeric to the deleted locus, including copy number gain (2- to 4-fold) of FOXG1 in 13 out of 16 tumors. This is associated with up-regulation (∼87-fold) of FOXG1 gene transcripts and increased protein expression. Immunostaining reveals an inverse relationship between FOXG1 expression and p21cip1 expression in all histologic subtypes. However, FOXG1 transcript levels were significantly higher (∼75-fold) in tumors with embryonal and small cell components when compared with pure fetal hepatoblastomas. FOXG1 has been implicated in the repression of transforming growth factor β–induced expression of p21cip1 and cytostasis. Our findings are consistent with such a role for FOXG1. We propose that FOXG1 overexpression may contribute to the maintenance of the undifferentiated state in hepatoblastomas and could be a potential target for molecular therapeutics. This is the first report of a possible role for FOXG1 in hepatoblastoma and pediatric neoplasia. [Copyright &y& Elsevier]

Objective: To differentiate developmental encephalopathies by creating a novel quantitative phenotyping tool.Study Design: We created the Developmental Encephalopathy Inventory (DEI) to differentiate disorders with complex multisystem neurodevelopmental symptoms. We then used the DEI to study the phenotype features of 20 subjects with FOXG1 disorder and 11 subjects with MECP2 disorder.Results: The DEI identified core domains of fine motor and expressive language that were severely impaired in both disorders. Individuals with FOXG1 disorder were overall more severely impaired. Subjects with FOXG1 disorder were less able to walk, had worse fine motor skills, more disability in receptive language and reciprocity, and had more disordered sleep than did subjects with MECP2 disorder (P <.05). Covariance, cluster, and principal component analysis confirmed a relationship between impaired awareness, reciprocity, and language in both disorders. In addition, abnormal ambulation was a first principal component for FOXG1 but not for MECP2 disorder, suggesting that impaired ambulation is a strong differentiating factor clinically between the 2 disorders.Conclusions: We have developed a novel quantitative developmental assessment tool for developmental encephalopathies and propose this tool as a method to identify and illustrate core common and differential domains of disability in these complex disorders. These findings demonstrate clear phenotype differences between FOXG1 and MECP2 disorders. [ABSTRACT FROM AUTHOR]