SEARCH · PubMed Health

Results for “Neural stem cells”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2025

Structural basis for the function of long noncoding RNA Pnky in neural stem cells.

LncRNA Pnky is a trans-acting regulator of neural stem cell (NSC) differentiation, but the molecular mechanisms by which Pnky regulates neurogenesis is unknown. A fundamental step towards mechanistic understanding is to determine whether a lncRNA has folded structure that underlies biological function. Using chemical probing and high-throughput analysis, we determined the secondary structure of Pnky folded in vitro and in cellulo. Pnky adopts a compact structure in vitro with distinct modules and evidence of tertiary interactions. In cellulo, Pnky structure is remarkably similar to the in vitro conformation. We used locked nucleic acid oligonucleotides to interrogate the entire Pnky transcript for function in NSCs and identified regions that when targeted increased neurogenesis - phenocopying Pnky knockdown - without decreasing transcript abundance. Our findings provide a structural basis for the role of Pnky in neurogenesis and, more broadly, illustrate how structural maps combined with phenotypic data can advance fundamental understanding of lncRNA mechanism.

LNA-ASOs↗

PubMed2026

Tailless terminates the neural stem cell temporal cascade in both the optic lobe and central brain.

Temporal patterning is an evolutionarily conserved mechanism to produce neuronal and glial diversity from common cells of origin during neurodevelopment. This process is controlled by a series of temporal transcription factors that are transiently expressed and drive the sequential production of specific progeny subtypes. Intermediate neural progenitors (INPs) and optic lobe neural stem cells (OL NSCs) share striking similarities in temporal factor expression despite divergent cells of origin. Tailless (Tll) is a terminal temporal factor in the visual system in OL NSCs. Its expression coincides with the termination of neurogenesis and onset of gliogenesis. Here, we report that Tll also acts as a terminal factor in Drosophila INPs, demonstrating functional conservation. Tll expression is activated by the preceding temporal factor Scarecrow, and represses odd-paired and hamlet. tll also plays a partial role in promoting gliogenesis in gliogenic NSCs. We performed genome-wide binding analysis of Tll in the OL NSCs and INPs by Targeted DamID, revealing both conserved and divergent targets, reflecting differences in regulatory outcomes. We show that temporal patterning mechanisms are conserved between different brain regions, whilst facilitating lineage-specific outputs.

Animals↗

PubMed2026

A human-specific non-coding RNA for EFHC1, an epilepsy-associated gene, regulates neural stem cell proliferation for cortical development.

Epilepsy is a prevalent brain disorder in humans but rarely occurs naturally in other species, highlighting the potential for human-specific mechanisms in its pathogenesis, and thus, current animal models fail to recapitulate human symptoms. Comparing RNA sequencing (RNA-seq) datasets from human and mouse neural stem cells (NSCs), we identified EFHC1, a juvenile myoclonic epilepsy gene, as exhibiting a human-biased expression. EFHC1 knockdown reduced human NSC proliferation, while its overexpression in mouse embryonic brains increased cortical NSC number. Mechanistically, EFHC1 prevented endoplasmic reticulum stress, thereby reducing inflammatory activation of p38 MAPK and promoting continuous proliferation of human NSCs. We also identified pancEFHC1, a bidirectional promoter-associated non-coding RNA (pancRNA), located at the human EFHC1 promoter. Knockdown of pancEFHC1 in human NSCs increased DNA methylation to reduce EFHC1 expression, with the resulting phenotype rescued by EFHC1 overexpression. We propose that the evolutionary acquisition of pancEFHC1 has introduced a complex regulatory mechanism for EFHC1 expression that allows distinguishing it in humans.

Humans↗

PubMed2026

Nrsn1-Smarcc1 Coupling Regulates Neural Stem Cell Differentiation and Chronic-phase Recovery After Ischemic Stroke.

Stroke remains a leading cause of long-term neurological disability worldwide, largely due to irreversible neuronal loss and the limited regenerative capacity of the adult mammalian brain. Neural stem cells (NSCs) in the adult brain possess the potential to generate new neurons after injury, yet the molecular mechanisms regulating their neuronal differentiation following ischemic insult remain incompletely understood. Here, integrating single-cell multi-omics analyses with spatial transcriptomics, we systematically delineated cell type-specific spatiotemporal dynamics in the striatum of a mouse model of ischemia-reperfusion injury. We identified Neurensin 1 (Nrsn1) as a gene markedly upregulated during NSC-derived neuronal differentiation in the recovery phase. Mechanistically, Foxa2 directly activates Nrsn1 transcription, whereas Nrsn1 promotes neuronal differentiation by facilitating the nuclear translocation of the chromatin-remodeling factor Smarcc1 in vitro. In vivo, both endogenous NSCs and transplanted NSCs overexpressing Nrsn1 significantly enhanced neuronal regeneration and improved functional recovery in mice subjected to middle cerebral artery occlusion and reperfusion (MCAO/R). Collectively, these findings identify Nrsn1 as a key regulator of NSC neuronal differentiation and uncover a Nrsn1-Smarcc1 coupling mechanism that promotes neural regeneration after ischemic brain injury, highlighting a potential molecular target for strategies aimed at enhancing post-stroke recovery.

Foxa2↗

PubMed2026

Manipulation of protein translation and stem cell self-renewal by CRISPR activation of rRNA transcription.

Ribosomal RNA (rRNA) transcription rates vary during development, and their dysregulation is linked to diseases such as cancer and ribosomopathies. Owing to their high abundance and genomic redundancy, the functional significance of rRNA levels remains unclear. We developed TAPIR (Targeted Activation of Protein Translation), a CRISPR-based approach to elevate rRNA levels by inducing 47S ribosomal DNA transcription. TAPIR increased nucleolar size and enhanced protein synthesis, even in rapidly proliferating cells. In neural stem cells, elevated translation promoted self-renewal and proliferation in vitro and in vivo. Furthermore, TAPIR enabled the modeling and partial rescue of associated disease phenotypes. Our findings reveal that rRNA levels directly regulate translational output and that protein synthesis capacity can act as a key determinant of mammalian stem cell behavior.

Animals↗

PubMed2025

Interrogating functional connectivity of in vitro neural glia tissue model modulated through integrative control of matrix stiffness and a neurotrophic factor.

Brain function emerges from intricate cellular communication within neural networks. Both In silico neuronal models and primary neuron cells have revealed that the branching architecture of individual neurons determines the bioelectrical signal propagation pattern and dynamics. However, whether stem cell-differentiated neurons can build functional connectivity regulated by neuronal morphology has yet to be determined. Here, we hypothesized that neurite length, branching, or both factors would regulate the functional connectivity of the stem cell-differentiated neural network. We examined this hypothesis by differentiating mouse cortical neural stem cells (NSCs) on Matrigel substrates with varying storage moduli, both with and without basic fibroblast growth factor (bFGF). Interestingly, with bFGF, Matrigel with a storage modulus (G') of 100 Pa drives NSCs to differentiate into neurons with more dendritic branches, while the gel with G' of 50 Pa led to the development of longer neurites with fewer branches. Notably, branch-rich neural networks exhibited an increased frequency of calcium transients. Using a MATLAB-based analysis pipeline incorporating graph theory, we constructed spatial and temporal calcium activity maps, revealing that branching complexity, more than neurite length, correlates with the density and strength of functional neural circuits. Overall, this study demonstrates that the dendritic branching of neurons, modulated with matrix stiffness and neurotrophic factors, is a key element in enhancing the electrophysiological functionality of the stem cell-differentiated neural network. This finding will have a significant impact on efforts to reconstruct functional neural tissue models, advancing both regenerative therapies and unexplored applications, including biological computing.

Animals↗

PubMed2025

Stem cell derived neural organoid approaches for neurological diseases.

Traditional two-dimensional cultures and animal models often fall short in capturing the complexities of neurodevelopmental and neurodegenerative diseases. However, recently developed neural organoid approaches, three-dimensional structures derived from human pluripotent stem cells, have become powerful tools for modeling human neuronal development and disease. Unlike traditional models, neural organoids provide significant insights and improved modeling capabilities. Here, we explore various types of neural organoids in disease modeling and outline distinct protocols for generating each type, including specific patterning methods, growth factors, and differentiation durations. The potential and advantages of co-culturing neural organoids with other cells and tissues are also discussed. While neural organoids have already made significant contributions to neuroscience research, future directions should focus on enhancing their maturation and functionality. The progression of neural organoids approaches will generate more accurate and comprehensive disease models, ultimately adding to our understanding of disease pathogenesis and paving the way for future precision therapies for neurological diseases.

neural differentiation↗

PubMed2024

A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex.

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

Animals↗

PubMed2025

CLADES: A Programmable Cascade of Genes for Cell Lineage Analysis and Manipulation.

In the Drosophila brain, neuronal diversity originates from approximately 100 neural stem cells, each dividing asymmetrically. Precise mapping of cell lineages at the single-cell resolution is crucial for understanding the mechanisms that direct neuronal specification. However, existing methods for high-resolution lineage tracing are notably time-consuming and labor-intensive. Here, we outline the best practices for lineage tracing using CLADES (cell lineage access driven by an edition sequence), a revolutionary approach to neuronal lineage tracing that addresses the limitations of previous methods. CLADES effectively traces the birth order of neurons using approximately 100 samples. The technique relies on a genetic cascade of reporter activations and deactivations that delineate lineage progression through color-coded markers. This system not only facilitates the detailed mapping of neuronal lineages but also holds the potential to be applied to tracking biological events and producing cell types for therapeutic purposes.

Animals↗

PubMed2026

Loss of function of the chromatin remodeling gene INO80D leads to neurogenic features of schizophrenia.

Schizophrenia has been linked to severely damaging de novo mutations in synaptic junction proteins, neurotransmitter receptors, transcription factors, and chromatin remodeling proteins. In a patient with schizophrenia in the absence of a family history of severe mental illness, we identified de novo nonsense mutation, INO80D p.Q568X, associated with both a truncated protein and partial nonsense-mediated decay. Three experiments were undertaken to evaluate the consequences of the mutation. 1) In neural stem cells (iNSCs) differentiated from WTC11 iPSCs, CRISPRi knockdown of INO80D led to downregulation of three subunits of the AMPA-glutamate receptor, of multiple genes mutant in schizophrenia, and of genes of synaptic function. 2) INO80D p.Q568X iNSCs and neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) had significantly lower expression of neurogenesis genes compared to patient-derived cells with the mutation corrected by CRISPR-Cas9 gene editing. Patient-derived INO80D p.Q568X neurons had significantly higher expression of cell division genes compared to lines with the mutation corrected, consistent with the possibility that some of these cells may be undergoing mitosis, which is not normal for neurons. 3) Finally, on microelectrode array (MEA) plates, WTC11-derived glutamatergic neurons with reduced expression of INO80D had more rapid firing rate and increased average network burst duration, both features of neurons derived from patients with neurodevelopmental disorders. Overall, these findings suggest that partial loss of INO80D function due to de novo mutation may have disrupted normal neurodevelopment and contributed to the schizophrenia of this patient.

Humans↗

PubMed2026

First-in-Class Small Molecule Inhibitor of Oncogene AVIL in Glioblastoma.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive malignant primary brain tumor, marked by rapid growth, extensive invasiveness, and a median survival of only ∼15 months despite current multimodal therapy. To identify new therapeutic vulnerabilities, we investigated the actin-regulatory protein AVIL, previously implicated through a MARS-AVIL gene fusion in rhabdomyosarcoma. Comprehensive genomic and transcriptomic analyses across REMBRANDT, TCGA, and CGGA datasets revealed recurrent AVIL amplification and consistently elevated AVIL expression in GBM compared with normal brain tissue. AVIL was overexpressed across all GBM molecular subtypes and glioma stem cell (GSC) states but was nearly undetectable in normal astrocytes, neural stem cells, and brain tissues. Functional studies demonstrated that AVIL is both necessary and sufficient for glioma genesis: AVIL silencing eradicated GBM cells in vitro and suppressed xenograft growth in vivo, while AVIL overexpression enhanced proliferation, migration, and transformation. Mechanistically, AVIL drives tumor progression through actin cytoskeleton remodeling and activation of the FOXM1-LIN28B oncogenic pathway. Using a small molecule microarray screen, we identified a selective AVIL-binding compound (compound A) that potently inhibited GBM cell growth with minimal toxicity to normal astrocytes. Gene expression changes induced by compound A mirrored those following AVIL knockdown, indicating on-target activity. Compound A demonstrated robust antitumor efficacy in multiple preclinical GBM models, including orthotopic xenografts, GSC-derived tumors, patient-derived xenografts, and temozolomide-resistant GBM with favorable pharmacokinetics and blood-brain barrier penetration. The minimal AVIL expression in normal tissues and lack of phenotype in AVIL-deficient mice underscore its potential as a low-toxicity therapeutic target. Together, these findings establish AVIL as a critical oncogenic driver in GBM and introduce a first-in-class AVIL inhibitor with strong translational promise for precision neuro-oncology.

Glioblastoma↗

PubMed2026

Quantitative proteomic profiling of neural cells-specific metabolic reprogramming in response to mitochondrial dysfunction using iMPAQT2.

Age-related mitochondrial dysfunction is increasingly recognized as a key contributor to neurodegenerative disease pathogenesis. In the central nervous system, neurons, oligodendrocytes, and astrocytes which derived from neural stem cells, fulfill distinct metabolic and functional roles. However, the specific vulnerabilities of these cell types to mitochondrial impairment remain unclear. In this study, we employed the iMPAQT2 proteomics platform to systematically compare the metabolic profiles of neurons, oligodendrocytes, and astrocytes, and to elucidate the molecular consequences of mitochondrial dysfunction induced by chloramphenicol and oligomycin. Our findings indicate that neurons and oligodendrocytes primarily rely on oxidative phosphorylation (OXPHOS) for ATP production, whereas astrocytes predominantly utilize glycolysis. It is noteworthy that oligodendrocytes exhibited enriched pathways for cholesterol synthesis, fatty acid degradation, and heme catabolism-processes that are critical for myelin maintenance. Treatment with the mitochondrial function inhibitors chloramphenicol or oligomycin reduced the expression of OXPHOS enzymes in all cell types. This reduction was particularly pronounced in oligodendrocytes for glycolysis, cholesterol synthesis, heme degradation, and fatty acid degradation. These results suggest that oligodendrocytes are particularly vulnerable to mitochondrial dysfunction, which may play a pivotal role in the pathogenesis of age-related neurodegenerative disorders.

Animals↗

PubMed2026

Putative glioblastoma origin-like cells in the subventricular zone: isolation and characterization.

Glioblastoma (GBM) remains lethal despite maximal therapy. The adult subventricular zone (SVZ), a neural stem-cell niche, has been implicated as a potential site of origin, yet the identity and functional properties of putative GBM origin-like cells (GBM-OCs) within the SVZ remain unclear. An SVZ-restricted somatic mutation mouse model (Cre-induced EGFRvIII expression with Trp53 and Pten disruption) was established and mouse SVZ-derived cells were prospectively isolated for functional and molecular profiling. Self-renewal, multipotency, invasive potential and tumour-initiating capacity were assessed relative to control SVZ cells and matched tumour-derived tumourspheres. Whole-genome and RNA sequencing defined genomic and transcriptional alterations during early progression. Mouse GBM-OCs exhibited self-renewal and multilineage differentiation and initiated tumours only after re-implantation into the SVZ (11/29, 38%), whereas direct striatal implantation failed (0/25, 0%), indicating context-dependent tumorigenic potential associated with the SVZ microenvironment. In contrast, tumour-derived tumourspheres retained tumorigenic capacity upon implantation into both the SVZ and the striatum. During progression from mouse GBM-OCs to tumours, whole-chromosome and arm-level aneuploidies accumulated. In patients with GBM, multi-region single-nucleus RNA sequencing of tumour-free SVZ, matched tumours and tumour-free cortex identified rare neural stem cell-like, astrocyte-like and oligodendrocyte precursor-like SVZ populations transcriptionally aligned with GBM programmes. These cells showed single-nucleus RNA-inferred chromosome 7 gain and/or chromosome 10 loss signals, with concordant low-frequency copy-number alterations in the SVZ detected by exome sequencing and enriched in matched tumours. Together, these findings support the presence of SVZ-resident stem or progenitor-like populations with early GBM-associated features, consistent with putative GBM-OCs, and highlight the SVZ niche as a potential target for early detection and niche-informed therapeutic strategies.

Animals↗

PubMed2025

Conserved lipid metabolic reprogramming confers hypoxic and aging resilience.

The Arctic ground squirrel (AGS, Urocitellus parryii), an extreme hibernator, exhibits remarkable resilience to stressors like hypoxia and hypothermia, making it an ideal model for studying cellular metabolic adaptation. The underlying mechanisms of AGS resilience are largely unknown. Here, we use lipidomic and metabolomic profiling to discover specific downregulation of triglyceride lipids and upregulation of the lipid biosynthetic precursor malonic acid in AGS neural stem cells (NSC) versus murine NSCs. Inhibiting lipid biosynthesis recapitulates hypoxic resilience of squirrel NSCs. Extending this model, we find that acute exposure to hypoxia downregulates key lipid biosynthetic enzymes in C. elegans, while inhibiting lipid biosynthesis reduces mitochondrial fission and facilitates hypoxic survival. Moreover, inhibiting lipid biosynthesis protects against APOE4-induced pathologies and aging trajectories in C. elegans. These findings suggest triglyceride downregulation as a conserved metabolic resilience mechanism, offering insights into protective strategies for neural tissues under hypoxic or ischemic conditions, APOE4-induced pathologies and aging.

Journal Article↗

PubMed2026

Microglial GRB2 is essential for brain ventriculogenesis and CSF homeostasis.

Microglia play essential yet poorly understood roles in brain development, including axon guidance, regulation of neurogenesis, and pruning of neuronal projections. Congenital hydrocephalus (CH), characterized by enlarged cerebrospinal fluid (CSF)-filled ventricles, is a leading cause of pediatric brain surgery, but its molecular mechanisms remain unclear. We have identified what we believe to be novel, recurrent, damaging missense variants in the SH3-binding domain of the adaptor protein Growth Factor Receptor-Bound Protein 2 (GRB2) in unrelated patients with CH. GRB2 is significantly co-expressed with one of its known upstream receptor tyrosine kinase partners, CSF1R, in the developing human brain, particularly in a microglial subtype associated with regulation of neural stem cells. Immunoprecipitation validated GRB2-CSF1R binding in mouse microglial cells and human monocyte cell line. Cx3cr1-Grb2fl/fl mice engineered with conditional deletion of Grb2 in microglia exhibit congenital absence of microglia and early postnatal severe communicating (non-obstructive) hydrocephalus, mimicking GRB2-mutant patients. The severe ventriculomegaly of Cx3cr1-Grb2fl/fl mice is associated with both depletion of cerebral cortical neurons and impairment of glia-lymphatic-mediated CSF flow. Together, these findings implicate a role of GRB2 in microglia that could be essential for brain development and CSF homeostasis.

Genetics↗

PubMed2026

CRISPR-Enabled functional genomics in hPSCs-derived neural models for autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.

Humans↗

PubMed2026

Brachyury expression levels predict lineage potential and axis-forming ability of in vitro-derived neuromesodermal progenitors.

Neuromesodermal progenitors (NMPs) produce the spinal cord and musculoskeleton in the elongating anterior-posterior axis. In vivo, NMPs possess dual potency, coinciding with regions co-expressing SOX2 and Brachyury (TBXT). In vitro, SOX2/TBXT co-expressing cells can be produced from pluripotent cells and, like their in vivo counterparts, can produce neural tube and somitic mesoderm. However, the functional characteristics of in vitro SOX2/TBXT co-expressing cells remain unclear, confounding comparisons with in vivo data. To address this, we developed a dual Sox2/Tbxt reporter mouse ESC line. SOX2/TBXT reporter-positive cells emerge in vitro from pluripotent populations with dynamics that mirror their appearance in the embryo. Purified SOX2/TBXT co-expressing populations can differentiate towards neurectoderm or mesoderm, including lateral mesoderm upon BMP stimulation. In gastruloids, quantitative live imaging shows that WNT or NOTCH inhibition rapidly leads to downregulation of TBXT expression and diminished axial extension. We show that clonally plated SOX2/TBXT co-expressing cells are bipotent NMPs that can also self-propagate. By combining clonal analysis with mathematical inference, we identify two thresholds of TBXT and/or SOX2 expression, switching clonal output from neural- to mesoderm-biased, and from mesoderm-biased to mesoderm-specified. Image analysis of embryonic NMPs supports a model whereby SOX2 and TBXT independently influence neuromesodermal differentiation. Thus, this Sox2/Tbxt double reporter cell line highlights unsuspected heterogeneity in NMPs, and together with image analysis of embryonic SOX2/TBXT levels, challenges the assumption that neuromesodermal fate choice is primarily governed by mutual antagonism between SOX2/TBXT.

Animals↗

PubMed2026

Thalamic NRXN1-mediated input to human cortical progenitors drives excitatory neurogenesis.

The human cerebral cortex develops through coordinated signals from within the cortex and from other brain regions, including the thalamus. However, how thalamic neuronal projections influence early human cortical development remains less well-understood. In this study, we fused cortical and thalamic organoids to investigate how thalamic input shapes the maturation of human cortical cells. Using single-nuclei RNA-sequencing and cellular imaging, we found that thalamic input increases the production of cortical excitatory neurons. We identify neurexin-1 (NRXN1) as a mediator of physical contact between thalamic axons and cortical outer radial glia. Genetic knockout of thalamic NRXN1 reduced these contacts and attenuated the production of upper-layer excitatory neurons. These findings reveal a mechanism by which thalamic input regulates human cortical progenitors and shapes excitatory neuron production during development.

Animals↗