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[Differentiation and regeneration on the subcellular level].
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Centriolo- and ciliogenesis in the rat's pituicytes under the influence of micrtubule poisons in vitro.
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The pineal gland of the mole (Talpa europaea L.) I. The fine structure of the pinealocytes.
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MeCP2 dysregulation inhibits mitophagy and impairs neural development in cortical organoids.
INTRODUCTION: Methylated CpG-binding protein 2 (MeCP2) plays a critical role in the normal development and function of the nervous system. Mutations in MeCP2 have been linked to neurodevelopmental disorders, potentially because of mitochondrial dysfunction and impaired mitophagy. However, the underlying mechanisms remain poorly understood. Investigating the role of MeCP2 in the regulation of mitophagy is essential for elucidating the pathogenesis of these disorders. OBJECTIVES: The aim of the present study was to explore the molecular mechanisms by which MeCP2 regulates mitophagy and determine how its dysfunction contributes to neurodevelopmental abnormalities using cortical organoids (COs) derived from MeCP2 mutant induced pluripotent stem cells (iPSCs). METHODS: CRISPR-Cas9 technology was used to generate MeCP2 mutant iPSCs, which were then differentiated into cortical organoids. Growth, proliferation, and differentiation of neural stem cells in these organoids were analysed. Single-cell RNA sequencing was performed to assess the changes in gene expression, focusing on mitophagy-related genes. MeCP2 occupancy at the BNIP3L transcription start site (TSS) was also examined. RESULTS: MeCP2 mutant COs exhibited growth inhibition, abnormal proliferation, and disrupted neural stem cell differentiation. Single-cell RNA sequencing revealed a significant downregulation of BNIP3L, a key mitophagy receptor. MeCP2 was found to occupy the BNIP3L TSS, leading to suppressed BNIP3L expression and impaired mitophagy in COs. CONCLUSION: The obtained findings demonstrate that MeCP2 regulates mitophagy by modulating BNIP3L expression, and its dysfunction leads to mitochondrial accumulation and neurodevelopmental abnormalities. The present study highlights the critical role of MeCP2 in maintaining mitochondrial homeostasis and provides insights into the molecular mechanisms underlying MeCP2-related neurodevelopmental disorders.
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Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia.
Malformations of the human cortex represent a major cause of disability1. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions2. Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with mutations in the cadherin receptor-ligand pair DCHS1 and FAT4 or from isogenic knockout (KO) lines1,3. Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1 and FAT4 or knockdown of their expression causes changes in the morphology of neural progenitor cells and result in defective neuronal migration dynamics only in a subset of neurons. Single-cell RNA-sequencing (scRNA-seq) data reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. We suggest that defective neural progenitor cell (NPC) morphology and an altered navigation system in a subset of neurons underlie this form of PH.
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Modeling Sporadic Progressive Supranuclear Palsy in 3D Midbrain Organoids: Recapitulating Disease Features for In Vitro Diagnosis and Drug Discovery.
OBJECTIVE: Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to model sporadic PSP-Richardson's syndrome (PSP-RS) using multi-donor midbrain organoids (MOs). METHODS: The MOs were generated by pooling induced pluripotent stem cells (iPSCs) from 4 patients with sporadic probable PSP-RS and compared them with MOs from 3 healthy control (HC) subjects. We performed comprehensive analyses of MOs over 120 days to assess neuronal death, reactive gliosis, and the accumulation of 4R-tau and hyperphosphorylated tau forms (pThr231, pSer396, pThr181, and pSer202/pThr205 [AT8]) using immunofluorescence microscopy and Western blot. On day 90, immunohistochemical analysis using pSer396 and AT8 antibodies was conducted to assess disease pathology. RESULTS: PSP-derived MOs showed progressive size reduction compared with HC-derived MOs, linked to upregulated apoptosis-related mRNA markers. Dopaminergic neuron degeneration was marked by decreased tyrosine hydroxylase (TH) and increased neurofilament light chain (NfL). Immunofluorescence and Western blot revealed accumulation of all investigated tau forms with a peak at 90 days, along with a significant rise in GFAP-positive cells in PSP-derived MOs. Immunochemistry confirmed typical PSP histological alterations, such as neurofibrillary tangles and tufted-shaped astrocytes, absent in HC-derived organoids. INTERPRETATION: We developed a robust in vitro PSP model reproducing the key molecular and histologic features of the disease. This result holds promise for advancing basic and clinical research in PSP, paving the way for in vitro molecular diagnosis and identification of novel therapeutic targets. ANN NEUROL 2025;97:845-859.
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Rapid and robust directed differentiation of mouse epiblast stem cells into definitive endoderm and forebrain organoids.
Directed differentiation of pluripotent stem cells (PSCs) is a powerful model system for deconstructing embryonic development. Although mice are the most advanced mammalian model system for genetic studies of embryonic development, state-of-the-art protocols for directed differentiation of mouse PSCs into defined lineages require additional steps and generates target cell types with lower purity than analogous protocols for human PSCs, limiting their application as models for mechanistic studies of development. Here, we examine the potential of mouse epiblast stem cells cultured in media containing Wnt pathway inhibitors as a starting point for directed differentiation. As a proof of concept, we focused our efforts on two specific cell/tissue types that have proven difficult to generate efficiently and reproducibly from mouse embryonic stem cells: definitive endoderm and neural organoids. We present new protocols for rapid generation of nearly pure definitive endoderm and forebrain-patterned neural organoids that model the development of prethalamic and hippocampal neurons. These differentiation models present new possibilities for combining mouse genetic tools with in vitro differentiation to characterize molecular and cellular mechanisms of embryonic development.
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The effect of dihydrotestosterone in combination with ovariectomy on intranuclear inclusions in mammotrophs of the Mongolian gerbil.
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Transcriptomic and metabolomic analyses reveal cobalt-induced mitochondrial metabolic alterations in human cortical organoids.
The global transition towards carbon-neutral energy systems has prompted a substantial increase in demand for cobalt (Co), making it a crucial component of lithium-ion batteries and advanced industrial materials. The widespread use and limited biological elimination of Co raises growing concerns regarding potential neurodevelopmental toxicity, yet the underlying mechanisms remain largely unresolved. Here, cortical organoids obtained from human induced pluripotent stem cells (iPSCs) were subjected to 5 - 20 μM CoCl2 for 28 days, with the integration of whole-transcriptomics, targeted-metabolomics, and microelectrode array (MEA). The present study has shown that Co exposure induced increased dose-dependent neural apoptosis and HIF-1α stabilization, while inhibiting neuronal generation. Multi-omics integration revealed disruption of tricarboxylic acid (TCA) cycle flux and the assembly of the mitochondrial energy metabolism respiratory chain, which may be mediated by long non-coding RNA (lncRNA)-mRNA interaction networks. These molecular and metabolic disturbances were accompanied by impaired oxidative phosphorylation (OXPHOS), reduced mitochondrial functional status, and ATP depletion. Synaptic immunostaining and MEA analysis further demonstrated that there was impaired formation of excitatory synapses and compromised electrophysiological function. Collectively, these findings provide a mechanistic basis for assessing the developmental neurotoxicity risks associated with Co and underscore the significance of epigenetic regulation of metabolic pathways as a plausible contributing factor from a human-relevant model.
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Vesicular transport of cationized ferritin by the epithelium of the rat choroid plexus.
We have studied the transport of ferritin that was internalized by coated micropinocytic vesicles at the apical surface of the choroid plexus epithelium in situ. After ventriculocisternal perfusion of native ferritin (NF) or cationized ferritin (CF), three routes followed by the tracers are revealed: (a) to lysosomes, (b) to cisternal compartments, and (c) to the basolateral cell surface. (a) NF is micropinocytosed to a very limited degree and appears in a few lysosomal elements whereas CF is taken up in large amounts and can be followed, via endocytic vacuoles and light multivesicular bodies, to dark multivesicular bodies and dense bodies. (b) Occasionally, CF particles are found in cisterns that may represent GERL or trans-Golgi elements, whereas stacked Golgi cisterns never contain CF. (c) Transepithelial vesicular transport of CF is distinctly revealed. The intercellular spaces of the epithelium, below the apical tight junctions, contain numerous clusters of CF particles, often associated with surface-connected, coated vesicles. Vesicles in the process of exocytosis of CF are also present at the basal epithelial surface, whereas connective tissue elements below the epithelium are unlabeled. Our conclusion is that fluid and solutes removed from the cerebrospinal fluid by endocytosis either become sequestered in the lysosomal apparatus of the choroidal epithelium or are transported to the basolateral surface. However, our results do not indicate any significant recycling via Golgi complexes of internalized apical cell membrane.