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PubMed2026

Fasudil induces anti-inflammatory transcriptomic changes and increased proliferation in human trisomy 21 neural progenitor cells.

Down syndrome (DS) results from trisomy for human chromosome 21 and is the most frequent genetic cause of intellectual disability. No effective treatments currently exist that improve neurodevelopment and cognition. Atypical brain development in individuals with DS is apparent before birth, which suggests that the optimal time to begin administration of therapies is prenatally. Human neural progenitor cell (NPC) cultures provide a tractable in vitro model system to examine the effects of trisomy 21 (T21) on neurodevelopment and to measure the effects of pharmacological interventions. Here, we report the results of preclinical studies evaluating 24 candidate therapies. RNA sequencing analyses found that euploid and T21 NPCs showed different transcriptomic responses to five candidate pharmacotherapies. The Rho-associated coiled-coil kinase inhibitor fasudil increased proliferation of T21 NPCs, reduced expression of inflammatory pathway genes in T21 NPCs, and reduced markers of inflammation in LPS-stimulated microglial model systems. These results demonstrate that fasudil can alter multiple T21-associated abnormalities in a beneficial manner, suggesting that fasudil warrants further study as a candidate prenatal pharmacotherapy for DS.

Down Syndrome↗
PubMed2025

Multicolor Cell Lineage Tracing Using MAGIC Markers Strategies.

Multicolor MAGIC Markers strategies are useful lineage tracing tools to study brain development at a multicellular scale. In this chapter, we describe an in utero electroporation method to simultaneously label multiple neighboring progenitors and their respective progeny using these multicolor reporters. In utero electroporation enables the introduction of any gene of interest into embryonic neural progenitors lining the brain ventricles through a simple pipeline consisting of a micro-injection followed by the application of electrical pulses. Successful in utero electroporation requires a concise yet complete understanding of each step of the surgical protocol, spanning from the preoperative preparation to the postoperative care, as well as the MAGIC Markers tool outlined in this study. Besides a detailed protocol, we present non-integrative and integrative approaches to demonstrate the range of cell and lineage tracking possibilities of multicolored progenitors and their descent over time.

Cell Lineage↗
PubMed2026

From wild to domestic: Single-cell transcriptomic perspectives on hippocampal regulation and evolution.

How domestication shapes brain evolution remains an open question. In this study, we integrated single-nucleus RNA sequencing (snRNA-seq), population genomics, and machine learning to investigate the hippocampal evolution under domestication. Across-species comparisons revealed that hippocampal cell type profiles are largely conserved across vertebrate species, while supporting the presence of adult hippocampal neurogenesis in birds. We further found that domestication and selective breeding likely influence the cellular composition and molecular regulation of the hippocampus. Our findings provide cellular evidence supporting the hypothesis that domestication affects adult hippocampal neurogenesis. Additionally, we showed that genes associated with neural progenitor cells (NPC) states and cell-marker programs are enriched for signatures of selection. Many of these genes function as regulators of neurogenesis and pathways mediating stress and fear reduction. Specifically, we identified selection at the FKBP5 promoter that may influence its expression in the NPC lineage, potentially contributing to stress-response regulation during domestication. Collectively, these results suggest that domestication is associated with hippocampal remodeling as part of an adaptive response to human-managed environments. This study provides a cellular and genetic perspective on how domestication reshapes the brain and offers a basis for further investigation into the mechanisms of neural evolution within the context of microevolution.

Animals↗
PubMed2024

Cell-type-specific loops linked to RNA polymerase II elongation in human neural differentiation.

DNA is folded into higher-order structures that shape and are shaped by genome function. The role of long-range loops in the establishment of new gene expression patterns during cell fate transitions remains poorly understood. Here, we investigate the link between cell-specific loops and RNA polymerase II (RNA Pol II) during neural lineage commitment. We find thousands of loops decommissioned or gained de novo upon differentiation of human induced pluripotent stem cells (hiPSCs) to neural progenitor cells (NPCs) and post-mitotic neurons. During hiPSC-to-NPC and NPC-to-neuron transitions, genes changing from RNA Pol II initiation to elongation are >4-fold more likely to anchor cell-specific loops than repressed genes. Elongated genes exhibit significant mRNA upregulation when connected in cell-specific promoter-enhancer loops but not invariant promoter-enhancer loops or promoter-promoter loops or when unlooped. Genes transitioning from repression to RNA Pol II initiation exhibit a slight mRNA increase independent of loop status. Our data link cell-specific loops and robust RNA Pol II-mediated elongation during neural cell fate transitions.

Humans↗
PubMed2026

cPRC1.2 and CTCF-mediated transition from poised to active chromatin loops at bivalent genes.

Polycomb Repressive Complex 1 (PRC1) and CCCTC-binding factor (CTCF) are critical regulators of 3D chromatin architecture that influence cellular transcriptional programs. Although the role of CTCF in chromatin organization is well-known, the involvement of PRC1 is less understood. In this study, we identify an unexpected role for the canonical Pcgf2-containing PRC1 complex (cPRC1.2) in activating bivalent genes. Hi-C revealed that cPRC1.2 forms chromatin loops at bivalent promoters, rendering them poised for activation. Pcgf2 deletion disrupts cPRC1.2 loops and impairs the transcriptional induction of crucial target genes necessary for neuronal differentiation. Furthermore, we identify CTCF enrichment at cPRC1.2 loop anchors and at Polycomb group (PcG) bodies, suggesting that PRC1 and CTCF cooperatively regulate chromatin loops. Through virtual 4C and other genomic analyses, we discover that establishing neuronal progenitor cell (NPC) identity involves a switch from cPRC1.2-mediated chromatin loops to CTCF-mediated active loops. Our results suggest a novel mechanism by which pre-formed PRC1 loops at lineage-specific genes maintain a poised state for subsequent CTCF-mediated active loops and gene activation in cell fate transitions.

CCCTC-Binding Factor↗
PubMed2025

Kin17 promotes rDNA transcription, ribosomal biogenesis, and cortical lamination.

During brain development, neural progenitor cells (NPCs) undergo rapid division, necessitating efficient ribosomal biogenesis for proliferation. Yet, the regulatory mechanisms remain largely elusive. Here, we report that the DNA binding protein Kin17 exhibits development-dependent expression and plays a vital role in embryonic development. Complete loss of Kin17 in mice leads to embryonic lethality, while Kin17 depletion specifically in NPCs allows embryonic survival but results in reduced brain size and cortical lamination defects. Our findings demonstrate that these cortical malformation stems from impaired NPC proliferation and differentiation. Mechanistically, we show that Kin17 binds to the promoter region of rDNA, sequentially recruiting NCL and Polr1a, thereby promoting rDNA transcription. Consequently, Kin17 facilitates ribosome biogenesis and protein translation in NPCs. This study underscores a critical role of Kin17 in promoting rDNA transcription and ribosomal biogenesis in NPCs during brain development, which is essential for proper cortical lamination.

Animals↗
PubMed2026

The DLX/Notch axis is necessary for spatiotemporal regulation of neural cell fate.

Neuronal-glial cell fate switch during forebrain development is highly regulated. DLX transcription factors are necessary for promoting GABAergic interneuron differentiation and migration but the mechanisms for concomitant repression of glial fate in neural progenitors remain elusive. Here, the DLX2 regulatory network dynamic in the developing ventral telencephalon is characterised using a multi-omic approach at single-cell resolution, including single-cell whole genome spatial transcriptomics. We identify a secondary proliferative zone in the ventral subventricular zone and spatiotemporal-context dependent Notch pathway repression by DLX2 in maintaining progenitor populations and facilitating neural differentiation. We find that DLX2 controls cell fate determination by directly repressing Notch signalling genes as well as glial fate-promoting transcription factors, thereby inhibiting early adoption of oligodendroglial differentiation during neurogenesis. Here, we show that temporal cell fate switch is mediated by DLX2 via a multilayer gene regulatory network, redefining current understanding of neuronal-glial cell specification mechanisms in the developing telencephalon.

Animals↗
PubMed2026

ATRX Condensates as Candidate Organizers of Enhancer-Centered Nuclear Microenvironments in Neural Progenitors: A Hypothesis for Enhancer-Associated ATRX Function in Neural Progenitors.

Neural progenitor cells (NPCs) must preserve lineage identity while remaining responsive to developmental cues. Here, we discuss the hypothesis that ATRX condensates help organize enhancer-centered nuclear microenvironments in NPCs. ATRX has long been studied in heterochromatin maintenance, histone variant deposition, and chromatin remodeling; earlier work has also shown that ATRX can occupy euchromatic and active regulatory regions and contribute to transcriptional regulation. Recent evidence in human NPCs indicates that ATRX forms nuclear puncta with condensate-like properties, associates with neurogenic enhancer-rich regions, and incorporates regulatory factors such as CHD7 and p300. Perturbation of ATRX condensate formation is associated with changes in enhancer-associated ATRX occupancy, neural gene-expression programs, and neuroepithelial organization, suggesting a regulatory mode that may complement canonical heterochromatin-associated functions. We propose a dual-mode model in which folded domains contribute to chromatin anchoring at repressive regions, whereas intrinsically disordered regions support condensate-associated organization at active developmental enhancers. We emphasize that whether ATRX condensates activate enhancers de novo, stabilize pre-existing enhancer states, buffer transcriptional variability, or primarily organize cofactor localization remains unresolved. We also discuss limitations of the current evidence and outline acute, locus-specific experiments needed to test the model.

X-linked Nuclear Protein↗
PubMed2025

Genetic and chromatin regulation of Pvt1 monoallelic expression.

While most genes are equivalently expressed on both alleles, genes with random monoallelic expression (RME) stably maintain expression from only one allele, but the mechanisms and consequences of RME remain unclear. We performed allele-specific RNA sequencing (RNA-seq) on ∼100 F1 hybrid neural progenitor cell (NPC) clonal lines to reveal the extent of autosomal RME (aRME). Of the 287 aRME genes, Pvt1, an oncogenic long non-coding RNA, is an aRME with a genetic bias. In the absence of genetic differences, Pvt1 undergoes balanced aRME. Pvt1 monoallelic expression is maintained by allele-specific active and repressive histone modifications, opposed to DNA methylation. Additionally, we provide a two-step mechanism for the initiation of aRME and demonstrate that Pvt1 monoallelic expression results in a growth phenotype due to the interplay with Myc. These findings provide insight into how genetic differences can skew a stochastic process, resulting in monoallelic expression with a phenotypic consequence in early development.

Chromatin↗
PubMed2026

BDNF-DT and BDNF-AS-DT: novel genes in the BDNF locus.

Divergent transcription from bidirectional promoters is frequently observed in eukaryotic genomes, but the biological relevance of divergent RNA transcripts (DT) is unknown. We identified and characterized BDNF-DT, a novel DT gene, and BDNF-AS-DT, a novel readthrough gene, in the locus containing BDNF, a gene with key roles in neuronal development, differentiation, and synaptic plasticity. BDNF-DT is independent from the known BDNF antisense (BDNF-AS), and its expression is developmentally regulated and positively correlated with BDNF in human postmortem dorsolateral prefrontal cortex (DLPFC). BDNF-DT and BDNF-AS-DT expression increase after induced depolarization, but the temporal dynamics follow expression of BDNF, suggesting a regulatory role. Moreover, CRISPR-mediated upregulation of BDNF in human neural progenitor cells drives BDNF-DT expression. Finally, BDNF-DT shows higher expression in DLPFC from patients diagnosed with schizophrenia compared to neurotypical controls, and genetically predicted lower expression of the BDNF-AS-DT readthrough transcript is associated with schizophrenia and with the schizophrenia-associated C allele of the rs6265 single-nucleotide polymorphism. These findings identify BDNF-DT and BDNF-AS-DT as novel, low-abundance genes that show coordinated expression with BDNF and association with schizophrenia risk, though their biological significance requires further validation given detection limitations and the need to establish causal roles.

Humans↗
PubMed1977

Differentiation of human neuroblastoma cells in vitro--morphological changes induced by dibutyrl cyclic AMP.

Differentiation ability of neuroblastoma cells was studied in vitro, light and electron microscopically using three continuously cultured cell lines (NB-1, GOTO, and YT-nu) of human origin. The cells ordinarily cultured appeared to differentiate along directions of both ganglionic and paraganglionic characterized by cytoplasmic catecholamine granules measuring 150 to 250 treatment with But2cAMP in NB-1 and YT-nu cells, but GOTO cells revealed only one-directed differentiation along ganglionic cell regardless of But2cAMP conditioning. Morphological and functional differentiation of mouse and human neuroblastoma cells in vitro, conversion of rat phenochromocytoma cells into sympathetic neurons in vitro, and ultrastructural differentiation of human neuroblastoma in vivo were discussed. In conclusion, neuroblastoma might be derived from a primitive stem cell of neural crest origin which possesses the pluripotency to be capable of differentiating along the sympathetic, parasympathetic, and other neural crest derivatives under certain conditions.

Adrenal Gland Neoplasms↗
PubMed1979

Primitive neuroectodermal tumor (neuroepithelioma) of spinal nerve root -- Report of an adult case and establishment of a cell line.

A case of primitive neuroectodermal tumor arising in the cervical nerve root of a 28-year-old man is presented. Histologically, the tumor was characterised by proliferation of primitive neuroectodermal cells and formation of numerous Homer-Wright type rosettes. A cell line (Nagai line) was established from the tumor. Electron microscopic examination of Nagai cells revealed numerous microrosette formation with microvilli-like cytoplasmic processes projecting into the central lumina. Neurosecretory granules appeared in the cytoplasmic processes when Nagai cells were treated with dibutyryl cyclic AMP. Primitive satellite cells which completely surrounded other tumor cells with their tongue-like slender cytoplasmic processes were also found. Histogenesis of this unique tumor was discussed comparing with the neuroblastoma of sympathetic nervous system, medulloblastoma of the central nervous system, and with the tumors induced by Adenovirus type 12 in animals. It was concluded that the tumor was neuroepithelioma derived from a primitive stem cell of neural crest origin which possesses the bipotency to differentiate toward either neuroblastic or neurilemmal line.

Adult↗
PubMed2026

A Patient-Derived iPSC-Based Model Reveals Neural Lineage-Specific Transcription of Endogenous HHV-6B.

BACKGROUND: Endogenous human herpesvirus 6 (eHHV-6), in which the entire viral genome is integrated into human chromosomes, is present in approximately 1% of the population and has been associated with various clinical conditions, including neurological disorders. However, its biological significance remains unclear due to the lack of appropriate experimental models. METHODS: We established a patient-derived induced pluripotent stem cell (iPSC)-based tissue culture model using lymphoblastoid cell lines from individuals with eHHV-6B. iPSCs retaining the integrated viral genome were generated and subsequently differentiated into neural stem cells (NSCs). Viral gene expression was evaluated by RT-qPCR under basal conditions and following chemical stimulation. RESULTS: The integrated HHV-6B genome was transcriptionally silent in iPSCs but exhibited spontaneous low-level expression of the immediate-early gene U90 and the late gene U100 in NSCs. Chemical stimulation further enhanced U90 expression, whereas induction of U100 did not reach statistical significance. These findings indicate preferential activation of early viral transcriptional programs in neural lineage cells. CONCLUSIONS: Neural lineage cells provide a permissive environment for expression of eHHV-6B transcripts. This patient-derived iPSC-based model provides a platform for investigating the biological significance of neural lineage-specific eHHV-6 transcripts and may facilitate interpretation of HHV-6 DNA detection in patients with eHHV-6 by enabling studies of cell type-dependent viral transcription.

endogenous HHV-6↗
PubMed2023

Cell type-specific loops linked to RNA polymerase II elongation in human neural differentiation.

DNA is folded into higher-order structures that shape and are shaped by genome function. The role for long-range loops in the establishment of new gene expression patterns during cell fate transitions remains poorly understood. Here, we investigate the link between cell-specific loops and RNA polymerase II (RNAPolII) during neural lineage commitment. We find thousands of loops decommissioned or gained de novo upon differentiation of human induced pluripotent stem cells (hiPSCs) to neural progenitors (NPCs) and post-mitotic neurons. During hiPSC-to-NPC and NPC-to-neuron transitions, genes changing from RNAPolII initiation to elongation are >4-fold more likely to anchor cell-specific loops than repressed genes. Elongated genes exhibit significant mRNA upregulation when connected in cell-specific promoter-enhancer loops but not invariant promoter-enhancer loops, promoter-promoter loops, or unlooped. Genes transitioning from repression to RNAPolII initiation exhibit slight mRNA increase independent of loop status. Our data link cell-specific loops and robust RNAPolII-mediated elongation during neural cell fate transitions.

Preprint↗
PubMed2026

Decoding glioblastoma evolution and heterogeneity through mechanistic modeling: implications for clinical translation.

Glioblastoma (GBM) is one of the most aggressive and lethal primary brain tumors in adults, characterized by dynamic clonal evolution and extensive genomic, cellular, spatial, and microenvironmental heterogeneity. Multi-omics studies have revealed that GBM follows complex evolutionary trajectories involving genetic, epigenetic, transcriptional, and immune-microenvironmental remodeling as tumors grow, adapt to the brain microenvironment, and acquire therapeutic resistance. Increasing evidence suggests that GBM may originate from aberrant neural stem or progenitor cells, including those residing in the subventricular zone, and that glioblastoma stem cells (GSCs) contribute to tumor propagation, heterogeneity, and recurrence. A key conceptual challenge is to reconcile hierarchical cancer stem cell models, in which GSCs are viewed as relatively stable tumor-propagating subpopulations, with dynamic state plasticity models, in which stem-like properties can be reversibly acquired or lost during transitions among proneural-like, mesenchymal-like, invasive, and therapy-tolerant states. Recent advances in single-cell profiling, spatial transcriptomics, lineage tracing, organoid culture, 3D bioprinting, genetically engineered models, and artificial intelligence (AI)-assisted computational modeling have substantially improved the ability to study these processes. However, no currently available model fully recapitulates human GBM heterogeneity, recurrence, treatment history, and tumor-microenvironment interactions. Therefore, model selection should be guided by clearly defined mechanistic questions rather than by reliance on any single platform. This review summarizes current advances in in vitro, ex vivo, in vivo, and computational models for studying GBM evolution and heterogeneity, and discusses how integrated model pipelines may improve preclinical drug testing, treatment-response prediction, and precision neuro-oncology.

Humans↗
PubMed2026

Progress on the telomere-telomerase system in planarian neoblasts homeostasis and regeneration.

Planarians are flatworms with remarkable regenerative abilities, and their adult pluripotent stem cells, known as neoblasts, serve as the foundation for this regeneration. Neoblasts can rapidly migrate, proliferate, and undergo directed differentiation following tissue injury to complete regeneration. Telomeres are located at the ends of eukaryotic chromosomes and play a core role in maintaining chromosomal integrity. With each cell division, telomeres shorten. Telomerase is a reverse transcriptase that compensates for telomere loss during cell division by extending telomeric repeats. The telomere-telomerase system is one of the important mechanisms for maintaining stem cell homeostasis. As adult pluripotent stem cells of planarians, neoblasts are required to maintain a dynamic balance between high-frequency cell division and multilineage differentiation. The maintenance of their long-term proliferative capacity and genomic stability may depend on the precise regulation of the telomere-telomerase system. Thus, this system represents a critical entry point for understanding the remarkable regenerative ability of planarians. Integrating recent progress in regeneration, neoblast regulation, and the telomere-telomerase system, we systematically summarize the emerging evidence for telomere- telomerase involvement in neoblast homeostasis and regeneration. We aim to provide insights for research in regenerative medicine, stem cell regulation, and neural injury repair.

Animals↗
PubMed2026

Endodermal Organoids Along Two Axes: Single-Organ Fidelity, Inter-Organ Reconstruction, and the Unbuilt Gut-Lung Frontier.

Three-dimensional organoids of the gut, liver, and lung have become mainstream models of human development, disease, and therapy. These organs share an embryonic endodermal origin, yet the field measures their progress inconsistently because the word "maturity" carries two unrelated meanings. Herein, we review the organoid work across all three organs and propose that the two orthogonal axes of advancement be analyzed separately. The first axis is single-organ fidelity. Adult stem cell organoids are faithful but partial, reproducing the adult epithelium of their source tissue with genomic stability yet lacking stromal, vascular, immune, and neural compartments. Human pluripotent stem cell organoids are complete but immature, co-emerging with multiple lineages yet arrested in a fetal-like state. The cost of each limitation is organ-dependent, smallest in the intestine, largest for hepatic drug metabolism, and most spatially defined across the proximal and distal lungs. The second axis is inter-organ reconstruction, where progress is strongly asymmetric. The gut-liver axis is comparatively advanced and sustained by linked organoid and microphysiological systems. The gut-lung axis, by contrast, remains the least-developed frontier, and no such linked organoid has yet been built. We therefore frame it as a proposal, using in vivo and correlative evidence to outline the design principles for such a model. Four bottlenecks recur across both axes: limited vascularization; batch-to-batch variability; organ-skewed immune, microbial, and stromal microenvironments; and unidirectional signaling. We argue that benchmarking models against single-cell developmental atlases and prioritizing construction of the gut-lung frontier should guide the field over the next decade.

Intestines↗
PubMed2026

A latent activated olfactory stem cell state revealed by single-cell transcriptomic and epigenomic profiling.

The olfactory epithelium is one of the few regions of the nervous system that sustains neurogenesis throughout life. Its experimental accessibility makes it especially tractable for studying molecular mechanisms that drive neural regeneration in response to injury. In this study, we used single-cell sequencing to identify transcriptional and epigenetic processes involved in determining olfactory epithelial stem cell fate during injury-induced regeneration. By combining gene expression and accessible chromatin profiles of individual lineage-traced olfactory stem cells, we identified transcriptional heterogeneity among activated stem cells at a stage when cell fates are being specified. We further identified a subset of resting cells that appears poised for activation, characterized by accessible chromatin around silent genes prior to their expression in response to injury. These results provide evidence for a latent activated stem cell state in which a subset of quiescent olfactory epithelial stem cells are epigenetically primed to support injury-induced regeneration.

Animals↗