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Evolutionary divergence in CTCF-mediated chromatin topology drives transcriptional innovation in humans.
Chromatin topology can impact gene regulation, but how evolutionary divergence in chromatin topology has shaped gene regulatory landscapes for distinctive human traits remains poorly understood. CTCF sites determine chromatin topology by forming domains and loops. Here, we show evolutionary divergence in CTCF-mediated chromatin topology at the domain and loop scales during primate evolution, elucidating distinct mechanisms for shaping regulatory landscapes. Human-specific divergent domains lead to a broad rewiring of transcriptional landscapes. Divergent CTCF loops concord with species-specific enhancer activity, influencing enhancer connectivity to target genes in a concordant yet constrained manner. Under this concordant mechanism, we establish the role of human-specific CTCF loops in shaping transcriptional isoform diversity, with functional implications for disease susceptibility. Furthermore, we validate the function of these human-specific CTCF loops using human forebrain organoids. This study advances our understanding of genetic evolution from the perspective of genome architecture.
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High-resolution transcriptional landscape of xeno-free human induced pluripotent stem cell-derived cerebellar organoids.
Current protocols for producing cerebellar neurons from human pluripotent stem cells (hPSCs) often rely on animal co-culture and mostly exist as monolayers, limiting their capability to recapitulate the complex processes in the developing cerebellum. Here, we employed a robust method, without the need for mouse co-culture to generate three-dimensional cerebellar organoids from hPSCs that display hallmarks of in vivo cerebellar development. Single-cell profiling followed by comparison to human and mouse cerebellar atlases revealed the presence and maturity of transcriptionally distinct populations encompassing major cerebellar cell types. Encapsulation with Matrigel aimed to provide more physiologically-relevant conditions through recapitulation of basement-membrane signalling, influenced both growth dynamics and cellular composition of the organoids, altering developmentally relevant gene expression programmes. We identified enrichment of cerebellar disease genes in distinct cell populations in the hPSC-derived cerebellar organoids. These findings ascertain xeno-free human cerebellar organoids as a unique model to gain insight into cerebellar development and its associated disorders.
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Three-dimensional midbrain organoids: a next-generation tool for Parkinson's disease modelling and drug discovery.
Parkinson's disease (PD), a progressive neurodegenerative disorder marked by dopaminergic (DA) neuron loss and Lewy body formation, lacks therapies to halt neurodegeneration. Current models, including 2D cultures and animal studies, fail to fully recapitulate human midbrain complexity, underscoring the need for advanced human-relevant disease modelling systems. Midbrain organoids (MOs), three-dimensional (3D) stem cell-derived neuronal structures mimicking midbrain architecture, have emerged as transformative tools for modelling PD. These organoids replicate key pathological hallmarks and enable disease mechanistic studies and drug screening for PD. Recent advances of research in MOs include genetic modelling of PD-linked mutations (e.g., LRRK2, GBA1, DNAJC6), optogenetics-assisted α-synuclein (α-syn) protein aggregation systems, and high-throughput drug testing platforms. MOs also show promise for cell replacement therapy, with successful integration and functional recovery in animal PD models. However, challenges such as batch variability, limited vascularization, incomplete neuronal maturation, and high costs hinder reproducibility and scalability. Future directions focus on integrating vascular networks, microglia co-cultures, automated workflows, and assembloid technologies to enhance pathophysiological relevance and translational potential in PD. By addressing these limitations, research in MOs could revolutionize PD research, offering critical insights into disease mechanisms and accelerating therapeutic discovery for PD patients.
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Parkinson's Disease Patient-Specific Striatum Organoids Show Hallmarks of Increased Inflammation.
BACKGROUND: Dopaminergic neurons from the substantia nigra pars compacta project their axons into the dorsal striatum, forming the nigrostriatal pathway. In Parkinson's disease (PD), dopaminergic terminals degenerate in the striatum, leading to dopamine depletion, which in turn causes alterations in the basal ganglia circuits that are essential for movement control. However, the reasons for dopaminergic neuron terminal degeneration in the striatum are still not understood. The LRRK2 gene is highly expressed in the striatum, and the LRRK2-G2019S mutation is one of the most common mutations associated with PD. It is therefore tempting to speculate that dysregulations in the striatal functionality can initiate or contribute to the dopaminergic neuron terminals' degeneration. OBJECTIVES: We aimed to examine the phenotypic differences between healthy and patient striatum organoids carrying the LRRK2-G2019S mutation to assess whether specific alterations in the striatum that are independent of dopaminergic input could contribute to the development of the disease. METHODS: Striatum organoids were generated using healthy and PD patient-induced pluripotent stem cell lines, and they were cultured until day 80. We evaluated the levels of striatum-specific proteins, and we performed proteomics and kinase activity analysis. RESULTS: PD striatum organoids revealed increased abundance of DRD2, DARPP32, and CDK5. Proteomics and kinase activity analysis demonstrated an inflammatory phenotype, which was further validated by investigating the occurrence of reactive astrocytes. CONCLUSIONS: Striatum organoids recapitulate PD-relevant phenotypes autonomously, independent of dopaminergic input. This includes a significant inflammatory phenotype. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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[Microtubular system in the nucleus of a hypothalamus neuron and its possible significance for fluids].
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Generation of Urine-Derived Induced Pluripotent Stem Cells and Cerebral Organoids for Modeling Down Syndrome.
Down syndrome (DS, or trisomy 21, T21), is the most common genetic cause of intellectual disability. Alterations in the complex process of cerebral cortex development contribute to the neurological deficits in DS, although the underlying molecular and cellular mechanisms are not completely understood. Human cerebral organoids (COs) derived from three-dimensional (3D) cultures of induced pluripotent stem cells (iPSCs) provide a new avenue for gaining a better understanding of DS neuropathology. In this study, we aimed to generate iPSCs from individuals with DS (T21-iPSCs) and euploid controls using urine-derived cells, which can be easily and noninvasively obtained from most individuals, and examine their ability to differentiate into neurons and astrocytes grown in monolayer cultures, as well as into 3D COs. We employed nonintegrating episomal vectors to generate urine-derived iPSC lines, and a simple-to-use system to produce COs with forebrain identity. We observed that both T21 and control urine-derived iPSC lines successfully differentiate into neurons and astrocytes in monolayer, as well as into COs that recapitulate early features of human cortical development, including organization of neural progenitor zones, programmed differentiation of excitatory and inhibitory neurons, and upper-and deep-layer cortical neurons as well as astrocytes. Our findings demonstrate for the first time the suitability of using urine-derived iPSC lines to produce COs for modeling DS.
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Ultrastructural organization of the mammalian pineal gland during postnatal ontogenesis.
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Lack of "synaptic" ribbons in the pineal gland of BALB/c mice.
In mammalian pinealocytes "synaptic" ribbons (SR) are regularly occurring organelles that are functionally poorly understood. Since in a number of studies on the mouse pineal gland the presence of SR has not been mentioned, it was the aim of this investigation to quantitate SR in mice. BALB/c mice were chosen, which have recently been shown to have a genetic defect for melatonin synthesis. The pineals of 15 mice killed at night, when SR numbers are normally high, were examined electron microscopically, scanning an area of greater than 20,000 micron 2 per gland. In none of these pineals were SR detected. It is concluded that the lack or extreme rarity of SR in laboratory mice may be related to the inability of the gland to synthesize melatonin, not to the absence of melatonin per se, as melatonin administration in mice does not result in the occurrence of SR.
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Characterization of human basal ganglia organoids.
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Localization of axonally transported label in chick retinal ganglion cell axons after intravitreal injections of wheat germ agglutinin conjugated to horseradish peroxidase.
We have studied the subcellular localization of peroxidase-labeled organelles after anterograde axonal transport by chick retinal ganglion cells that had been exposed 23-25 h earlier to wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP). After intravitreal injection of WGA-HRP, we found in the optic tectum that 82% of labeled organelles were located within axons and axon terminals. The organelles included: tubules and cisternae of the smooth endoplasmic reticulum, hypolemmal cisternae, vesicles, dense bodies and multivesticular bodies. We also measured the distances between the centers of the labeled organelles and the plasma membrane of these profiles. The density of organelles (number of organelles/micron 2) was plotted as a function of distance from the plasma membrane. Irrespective of the dose of lectin-peroxidase injected, labeled organelles were most densely concentrated in a 30 nm wide annular zone centered 75 nm in from the plasma membrane. In axon terminals the labeled organelles were most concentrated 75-90 nm in from the plasma membrane. Assuming that the peroxidase label indicates the presence of WGA-HRP, we conclude that after anterograde axonal transport the lectin accumulates in lysosomal organelles and elements of the smooth endoplasmic reticulum. Therefore, in contrast to the more restricted localization of [125I]WGA as inferred from electron microscopic autoradiography after uptake and transport by the same cell type, WGA-HRP-labeled organelles are found more diffusely within the axoplasm, particularly in axon terminals. Furthermore, peroxidase-labeled organelles in dendritic, glial or neuronal cell bodies in the tectum were seen less frequently than expected based on evidence of frequent transfer to second cells after intravitreal injections of [125I]WGA. Thus, we infer that at these concentrations WGA labeled with HRP may not be transferred intercellularly as efficiently as even lower concentrations of iodinated WGA are apparently transferred.