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Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P

It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer.

Autophagy and energy metabolism are known to follow a circadian pattern. However, it is unclear whether autophagy and the circadian clock are coordinated by common control mechanisms. Here, we show that the oscillation of autophagy genes is dependent on the nutrient-sensitive activation of TFEB and TFE3, key regulators of autophagy, lysosomal biogenesis, and cell homeostasis. TFEB and TFE3 display a circadian activation over the 24-h cycle and are responsible for the rhythmic induction of genes involved in autophagy during the light phase. Genetic ablation of TFEB and TFE3 in mice results in deregulated autophagy over the diurnal cycle and altered gene expression causing abnormal circadian wheel-running behavior. In addition, TFEB and TFE3 directly regulate the expression of Rev-erbα (Nr1d1), a transcriptional repressor component of the core clock machinery also involved in the regulation of whole-body metabolism and autophagy. Comparative analysis of the cistromes of TFEB/TFE3 and REV-ERBα showed an extensive overlap of their binding sites, particularly in genes involved in autophagy and metabolic functions. These data reveal a direct link between nutrient and clock-dependent regulation of gene expression shedding a new light on the crosstalk between autophagy, metabolism, and circadian cycles.

Simple Summary: In this study, we sought to understand the role of NF2 gene mutation in the carcinogenesis of sporadic cancers. NF2 gene mutations are noted in several central nervous system tumors, solid-organ tumors, and skin cancers. We conducted a literature review on eleven different cancers with NF2 gene mutation involvement, summarizing the extent of association and specific biological pathways thought to be affected by NF2 mutations. We synthesized studies across several oncologic fields to consolidate what we know about NF2 gene mutations in cancer development. The Hippo signaling pathway is a biological pathway that is involved in eight of the eleven NF2-mutated cancers studied in this review. Although NF2 mutation has a known interaction with the Hippo signaling pathway, the specific details of this interface remain a topic for further studies. Background/Objectives: With the rise in prevalence of diagnostic genetic techniques like RNA sequencing and whole exome sequencing (WES), as well as biological treatment regiments for cancer therapy, several genes have been implicated in carcinogenesis. This review aims to update our understanding of the Neurofibromatosis 2 (NF2) gene and its role in the pathogenesis of various cancers. Methods: A comprehensive search of five online databases yielded 43 studies that highlighted the effect of sporadic NF2 mutations on several cancers, including sporadic meningioma, ependymoma, schwannoma, mesothelioma, breast cancer, hepatocellular carcinoma, prostate cancer, glioblastoma, thyroid cancer, and melanoma. Of note were key biological pathways implicated in cancer formation resulting from sporadic NF2 mutations. Results: NF2 gene mutations are implicated in over 11 different cancers, including several CNS tumors, soli-organ tumors, and skin cancer. NF2 acts as a driver mutation in some cancers, as a non-driver mutation in some cancers, and has simple associated mutations with other cancers. In terms of biological pathway involvement, 8 of the 11 cancers with NF2 mutations show evidence of Hippo signaling cascade involvement. Conclusions: Several cancers characterized by mutations in the NF2 gene have associations with the Hippo signaling pathway. However, future studies remain to be done to further elucidate the role of the Hippo signaling pathway in the carcinogenesis of human NF2-mutant tumors. The findings of this review provide insights into the role of NF2 mutations in cancers, Hippo signaling in NF2-mutant cancers, and current gaps in our knowledge regarding the two. [ABSTRACT FROM AUTHOR]

Alterations in gene dosage due to copy number variation are associated with autism spectrum disorder, intellectual disability (ID), and other psychiatric disorders. The nervous system is so acutely sensitive to the dose of methyl-CpG-binding protein 2 (MeCP2) that even a twofold change in MeCP2 protein-either increased or decreased-results in distinct disorders with overlapping features including ID, autistic behavior, and severe motor dysfunction. Rett syndrome is caused by loss-of-function mutations in MECP2, whereas duplications spanning the MECP2 locus result in MECP2 duplication syndrome (MDS), which accounts for ~1% of X-linked ID. Despite evidence from mouse models that restoring MeCP2 can reverse the course of disease, there are currently no U.S. Food and Drug Administration-approved therapies available to clinically modulate MeCP2 abundance. We used a forward genetic screen against all known human kinases and phosphatases to identify druggable regulators of MeCP2 stability. Two putative modulators of MeCP2, HIPK2 (homeodomain-interacting protein kinase 2) and PP2A (protein phosphatase 2A), were validated as stabilizers of MeCP2 in vivo. Further, pharmacological inhibition of PP2A in vivo reduced MeCP2 in the nervous system and rescued both overexpression and motor abnormalities in a mouse model of MDS. Our findings reveal potential therapeutic targets for treating disorders of altered MECP2 dosage.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2005.12.037 Byline: Tiemo J. Klisch, Jacob Souopgui, Kathrin Juergens, Barbara Rust, Tomas Pieler, Kristine A. Henningfeld Keywords: Xenopus; Primary neurogenesis; Mad; Myc; Sox Abstract: We have isolated and characterized Xenopus Mxi1, a member of the Myc/Max/Mad family of bHLHZip transcription factors. Xmxi1 transcripts are present during gastrulation and early neurula stages, earlier and in broader domains as compared to the neuronal determination factor neurogenin (X-ngnr-1). Consistent with an early role in neurogenesis, Xmxi1 is positively regulated by Sox3, SoxD, and proneural genes, as well as negatively by the Notch pathway. Loss-of-function experiments demonstrate an essential role for Xmxi1 in the establishment of a mature neural state that can be activated by factors that induce neuronal differentiation, such as SoxD and X-ngnr-1. Overexpression of Xmxi1 in Xenopus embryos results in ectopic activation of Sox3, an early pan-neural marker of proliferating neural precursor cells. Within the neural plate, the neuronal differentiation marker N-tubulin and cell cycle control genes such as XPak3 and p27(Xic1) are inhibited, but the expression of early determination and differentiation markers, including X-ngnr-1 and X-MyT1, is not affected. Inhibition of neuronal differentiation by Xmxi1 is only transient, and, at early tailbud stages, both endogenous and ectopic neurogenesis are observed. While Xmxi1 enhances cell proliferation and apoptosis in the early Xenopus embryo, both activities appear not to be required for the function of Xmxi1 in primary neurogenesis. Author Affiliation: DFG-Center of Molecular Physiology of the Brain, Department of Developmental Biochemistry, University of Gottingen, Justus-von-Liebig Weg 11, 37077 Gottingen, Germany Article History: Received 3 November 2005; Revised 14 December 2005; Accepted 16 December 2005

Atonal homolog 1 (Atoh1) is a basic helix-loop-helix (bHLH) transcription factor that is essential for the genesis, survival, and maturation of a variety of neuronal and non-neuronal cell populations, including those involved in proprioception, interoception, balance, respiration, and hearing. Such diverse functions require fine regulation at the transcriptional and protein levels. Here, we show that serine 193 (S193) is phosphorylated in Atohl'sbHLH domain in vivo. Knock-in mice of both sexes bearing a GFP-taggedphospho-deadS193A allele on a null background (AtohlS193A/latZ) exhibit mild cerebellar foliation defects, motor impairments, partial pontine nucleus migration defects, cochlear hair cell degeneration, and profound hearingloss. We also found that Atoh 1 heterozygous mice of both sexes (Atoh1lacZ/+) have adult-onset deafness. These data indicate that different cell types have different degrees of vulnerability to loss of Atohl function and that hypomorphic Atoh1 alleles should be considered in human hearing loss. [ABSTRACT FROM AUTHOR]

Hair cells are sensory receptors for the auditory and vestibular system in vertebrates. The transcription factor Atohl is both necessary and sufficient for the differentiation of hair cells, and is strongly upregulated during hair-cell regeneration in nonmammalian vertebrates. To identify genes involved in hair cell development and function, we performed RNA-seq profiling of purified Atoh1-expressing hair cells from the neonatal mouse cochlea. We identified >600 enriched transcripts in cochlear hair cells, of which 90% have not been previously shown to be expressed in hair cells. We identified 233 of these hair cell genes as candidates to be directly regulated by Atoh1 based on the presence of Atoh1 binding sites in their regulatory regions and by analyzing Atoh1 ChIP-seq datasets from the cerebellum and small intestine. We confirmed 10 of these genes as being direct Atoh1 targets in the cochlea by ChIP-PCR. The identification of candidate Atoh1 target genes is a first step in identifying gene regulatory networks for hair-cell development and may inform future studies on the potential role ofAtoh1 in mammalian hair cell regeneration. [ABSTRACT FROM AUTHOR]

Neural basic helix-loop-helix (bHLH) transcription factors are crucial in regulating the differentiation and neuronal subtype specification of neurons. Precisely how these transcription factors direct such processes is largely unknown due to the lack of bona fide targets in vivo. Genetic evidence suggests that bHLH factors have shared targets in their common differentiation role, but unique targets with respect to their distinct roles in neuronal subtype specification. However, whether neuronal subtype-specific targets exist remains an unsolved question. To address this question, we focused on Atoh1 (Math1), a bHLH transcription factor that specifies distinct neuronal subtypes of the proprioceptive pathway in mammals including the dI1 (dorsal interneuron 1) population of the developing spinal cord. We identified transcripts unique to the Atoh1-derived lineage using microarray analyses of specific bHLH-sorted populations from mouse. Chromatin immunoprecipitation-sequencing experiments followed by enhancer reporter analyses identified five direct neuronal subtype-specific targets of Atoh1 in vivo along with their Atoh1-responsive enhancers. These targets, Klf7, Rab15, Rassf4, Selm, and Smad7, have diverse functions that range from transcription factors to regulators of endocytosis and signaling pathways. Only Rab15 and Selm are expressed across several different Atoh1-specified neuronal subtypes including external granule cells (external granule cell layer) in the developing cerebellum, hair cells of the inner ear, and Merkel cells. Our work establishes on a molecular level that neuronal differentiation bHLH transcription factors have distinct lineage-specific targets. [ABSTRACT FROM AUTHOR]

Background: World Health Organization Grade 2 meningiomas (G2Ms) often recur and resist therapies. G2Ms with histopathological necrosis have been associated with worse local control (LC) following radiation therapy, but the drivers and biomarkers of radiation resistance in G2Ms remain unknown., Methods: We performed genetic sequencing and histopathological analysis of 113 G2Ms and investigated the role of genetic and microenvironmental factors on clonogenic survival following ionizing radiation. We performed transcriptional profiling of our in vitro model and 18 human G2M tumors by bulk RNA sequencing as well as eight G2Ms by single nuclei RNA sequencing., Results: NF2 loss-of-function (LOF) mutations were associated with necrosis in G2Ms (p = .0127). Tumors with NF2 mutation and necrosis had worse post-radiation LC compared to NF2 wildtype tumors without necrosis (p = .035). Under hypoxic conditions, NF2 knockdown increased radiation resistance in vitro (p < .001). Bulk RNA sequencing revealed NF2- and hypoxia-specific changes and a 50-gene set signature specific to radiation resistant, NF2 knockdown and hypoxic cells, which distinguished NF2 mutant/necrotic patient G2Ms by unsupervised clustering. Enrichment analysis revealed downregulation of apoptosis pathway genes and upregulation of proliferation-associated genes and genes normally downregulated after UV radiation exposure in NF2-mutant/necrotic tumor cells, which were validated with functional assays., Conclusions: NF2 LOF in the setting of hypoxia confers radiation resistance through transcriptional programs that reduce apoptosis and promote proliferation. These pathways may identify tumors resistant to radiation and represent therapeutic targets that in the future could improve LC in patients with radiation resistant G2Ms., (© The Author(s) 2025. Published by Oxford University Press.)