Ontology highlight
ABSTRACT:
PROVIDER: PRJNA140341 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:With the advent of exome sequencing, a growing number of children are being identified with de novo loss of function mutations in the large GTPase essential for mitochondrial fission - Dynamin Related Protein 1 (DRP1); these mutations result in severe neurodevelopmental phenotypes such as developmental delay, optic atrophy, and epileptic encephalopathies. Though it is established that mitochondrial fission is an essential precursor to the rapidly changing metabolic needs of the developing cortex, it is not understood how identified mutations in different domains of DRP1 uniquely disrupt cortical development and synaptic maturation. We leveraged the power of both high-resolution imaging and induced pluripotent stem cells (iPSCs) harboring DRP1 mutations in either the GTPase or stalk domains to model early stages of cortical development. Transcriptional profiling of mutant DRP1 cortical neurons during maturation, as well as imaging of organelle dynamics and neuronal synapses, strongly suggests that altered mitochondrial morphology of DRP1 mutant neurons affect synaptic development leading to pathogenic dysregulation of synaptic activity.
2025-06-30 | GSE296512 | GEO
Project description:One of the most salient features of human brain development is the considerably prolonged, neotenic, timing of synaptic development compared to other mammals including non-human primates. Microglia play key roles in shaping synaptic connectivity during neural circuits development. However, the structural and functional features of human microglia maturation remain poorly studied. Here, we first demonstrate that human and mouse cortical microglia follow similar developmental trajectories, albeit at strikingly different timescales in vivo. The ancestral gene SRGAP2A and its human-specific paralogs SRGAP2B/C are not only expressed in cortical neurons where they control the timing of synaptic maturation but also that SRGAP2B/C are the only human-specific gene duplications (HSGDs) expressed in human microglia. Using combinations of xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia and mouse genetic models, we demonstrate that (1) HS SRGAP2B/C, by inhibiting SRGAP2A, are necessary and sufficient to induce neotenic features of microglia structural maturation through microglia-specific manipulations, and (2) that induction of SRGAP2-dependent neotenic features of microglia maturation impacts the timing of synaptic development in a non-cell autonomous manner. Taken together with previous studies, our results reveal that, during human brain evolution, the human-specific genes SRGAP2B/C coordinated the emergence of neotenic features of synaptic development by acting as genetic modifiers in both neurons and microglia.
2026-06-20 | GSE335485 | GEO
Project description:We search for developmental changes specific to humans by examining gene expression profiles in the human, chimpanzee and rhesus macaque prefrontal and cerebellar cortex. In both brain regions, developmental patterns were more evolved in humans than in chimpanzees. The major human specific genes in prefrontal cortex was enriched in neuronal functions and regulated by several transcription factors, which were previously implicated in regulation of neuronal functions. To confirm neuronal function of the human prefrontal cortex specific genes, we identifed response genes upon neuronal activation in mouse cortical neurons. Our results show that human specific genes are enriched in the response genes upon neuronal activation, implying the function of human prefrontal cortex specific genes in synaptic development. The cortical neurons from E15 mouse were isolated and cultured. We then exposed neurons to bicuculline (Bic), or potassium chloride (KCl), or without treatment. The cultured neurons under each group were hybridized to Agilent whole mouse genome oligo microarray (4x44k).
2012-02-02 | E-GEOD-29139 | biostudies-arrayexpress
Project description:Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy and seizures. NGLY1’s activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons, but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.
2024-05-23 | PXD031091 | Pride
Project description:Two key paradigms for examining activity-dependent development of primary visual cortex (V1) involve either reduction of activity in both eyes via dark-rearing (DR) or imbalance of activity between the two eyes via monocular deprivation (MD).,Combining DNA microarray analysis with computational approaches, RT-PCR, immunohistochemistry and physiological imaging, we find that DR leads to (i) upregulation of genes subserving synaptic transmission and electrical activity, consistent with a coordinated response of cortical neurons to reduction of visual drive, and (ii) downregulation of parvalbumin, implicating parvalbumin-expressing neurons as underlying the delay in cortical maturation after DR. MD partially activates homeostatic mechanisms but differentially upregulates gene systems related to growth factors and neuronal degeneration, consistent with reorganization of connections after MD. A binding protein of Insulin-like Growth Factor 1 is highly upregulated after MD, and exogenous application of IGF1 prevents the physiological effects of MD on ocular dominance plasticity examined in vivo.
2007-07-07 | E-GEOD-4537 | biostudies-arrayexpress
Project description:We search for developmental changes specific to humans by examining gene expression profiles in the human, chimpanzee and rhesus macaque prefrontal and cerebellar cortex. In both brain regions, developmental patterns were more evolved in humans than in chimpanzees. To distinguish whether the human specific developmental pattern represent novel human-specific developmental patterns or a shift in the timing of the existing patterns, we measured mRNA expression patterns in macaque brains from prenatal to neonatal. Our results show that the major human-specific developmental patterns identified in the PFC reflects an extreme shift in timing of synaptic development.
2012-02-02 | GSE29138 | GEO
Project description:The mammalian cortex is the structural basis for learning, cognition, and movement coordination. Dysgenesis of axon dendrites and synapses in cortical neurons can hinder learning and cognitive development, leading to epilepsy. Transcription factor Otx1 plays an important role in the development of the morphology and electrophysiological activity of cortical neurons and is associated with the occurrence of epilepsy. Abnormal synaptic pruning has been proposed to be one of the molecular mechanisms underlying epilepsy. Otx1 mutant mice leads to defective axonal pruning and changes the excitability and synaptic connections of the cortical neurons. However, little is known about the molecular pathways through which the loss of Otx1 causes epilepsy. On this basis, we found that the density and morphology of dendritic spines and microglia in Otx1 mutant mice changed significantly. TMT analysis of synaptic proteins reveals that Otx1 regulates the structure and function of cortical neurons and synaptic characteristics by regulating microglia-mediated synaptic pruning through the complement system, which also has important theoretical significance and application value for effective prevention and treatment of epilepsy.
2023-04-15 | PXD041568 |
Project description:We search for developmental changes specific to humans by examining gene expression profiles in the human, chimpanzee and rhesus macaque prefrontal and cerebellar cortex. In both brain regions, developmental patterns were more evolved in humans than in chimpanzees. To distinguish whether the human specific developmental pattern represent novel human-specific developmental patterns or a shift in the timing of the existing patterns, we measured mRNA expression patterns in macaque brains from prenatal to neonatal. Our results show that the major human-specific developmental patterns identified in the PFC reflects an extreme shift in timing of synaptic development. Rhesus macaque post-mortem brain samples from the superior frontal gyrus region of the prefrontal cortex were collected. Six fetal and six newborn samples were used. RNA extracted from the dissected tissue was hybridized to Affymetrix® Human Gene 1.0 ST arrays.
2012-02-02 | E-GEOD-29138 | biostudies-arrayexpress
Project description:Voltage-gated sodium channels regulate neuronal excitability and fast synaptic transmission in the postnatal and adult brain. The gene SCN2A, encoding the sodium channel Nav1.2, regulates synaptic development and variants in SCN2A are associated with autism spectrum disorders (ASD). The expression pattern of SCN2A begins during fetal cortical development, prior to the onset of synaptic transmission, but it is unknown whether SCN2A regulates early cortical development through mechanisms independent of synaptic transmission. Here we reveal that isogenic and ASD patient-derived human forebrain organoids modelling a loss of SCN2A function display impaired excitatory and inhibitory neurogenesis, leading to a developmental imbalance. Unexpectedly, we find precocious generation of cortical inhibitory neurons is driven by elevated sonic hedgehog (SHH) signaling and is reversible through pharmacological inhibition. Functionally, these developmental phenotypes arise due to sodium channel dysfunction and lead to abnormal neuronal network activity. Our results identify a new mechanisim for cortical excitatory and inhibitory neurogenesis involving SCN2A, and reveal that early neurogenesis deficits precedes postnatal neural circuit dysfunction in SCN2A-associated disorders.
2026-06-09 | GSE292644 | GEO
Project description:Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy and seizures. NGLY1’s activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons, but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.
2025-02-13 | GSE197454 | GEO