Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1088504 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:A phenotypic brain organoid atlas for neurodevelopmental disorders
| PRJNA1084812 | ENA
Project description:GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders Organoid SC
2024-06-27 | E-MTAB-13478 | biostudies-arrayexpress
Project description:The mammalian telencephalon plays critical roles in cognition, motor function, and emotion. While many of the genes required for its development have been identified, the distant‐acting regulatory sequences orchestrating their in vivo expression are mostly unknown. Here we describe a digital atlas of in vivo enhancers active in subregions of the developing telencephalon. We identified over 4,600 candidate embryonic forebrain enhancers and studied the in vivo activity of 329 of these sequences in transgenic mouse embryos. We generated serial sets of histological brain sections for 145 reproducible forebrain enhancers, resulting in a publicly accessible web‐based enhancer atlas comprising over 33,000 sections. We show how this large collection of annotated telencephalon enhancers can be used to study the regulatory architecture of individual genes, to examine the sequence motif content of enhancers, and to drive targeted reporter or effector protein expression in experimental applications. Furthermore, we used epigenomic analysis of human and mouse cortex tissue to directly compare the genome‐wide enhancer architecture in these species. This atlas provides a primary resource for investigating gene regulatory mechanisms of telencephalon development and enables studies of the role of distant‐acting enhancers in neurodevelopmental disorders. Examination of p300 binding in mouse embryonic stage 11.5 forebrain, mouse postnatal (P0) cortex tissue and human fetal (gestational week 20) cortex
2013-01-29 | E-GEOD-42881 | biostudies-arrayexpress
Project description:Astroglia are integral to brain development and the emergence of neurodevelopmental disorders. However, studying the pathophysiology of human astroglia using brain organoid models has been hindered by inefficient astrogliogenesis. In this study, we introduce a robust method for generating astroglia-enriched organoids through BMP4 treatment during the neural differentiation phase of organoid development. Our RNA sequencing analysis reveals that astroglia developed within these organoids exhibit advanced developmental characteristics and enhanced synaptic functions compared to those grown under traditional two-dimensional conditions, particularly highlighted by increased neurexin (NRXN)-neuroligin (NLGN) signaling. Cell adhesion molecules, such as NRXN and NLGN, are essential in regulating interactions between astroglia and neurons. We further discovered that brain organoids derived from human embryonic stem cells (hESCs) harboring the autism-associated NLGN3 R451C mutation exhibit increased astrogliogenesis. Notably, the NLGN3 R451C astroglia demonstrate enhanced branching, indicating a more intricate morphology. Interestingly, our RNA sequencing data suggest that these mutant astroglia significantly upregulate pathways that support neural functions when compared to isogenic wild-type astroglia. Our findings establish a novel astroglia-enriched organoid model, offering a valuable platform for probing the roles of human astroglia in brain development and related disorders.
2024-12-08 | GSE283484 | GEO
Project description:5-hydroxymethylcytosine (5hmC) endures dynamic changes during mammalian brain development and its aberrant regulation is known to be associated with numerous neurological diseases such as Alzheimer’s Disease (AD). Recent evidence suggests that key epigenetic changes could occur during neural development long before the onset of neurodegenerative disorders. However, the dynamics of 5hmC during early human brain development and how that contributes to pathogenesis of neurodegeneration, particularly AD pathologies, remain largely unexplored. To investigate this, we utilized the human iPSC-derived organoid model. We derived the 5hmC and transcriptome profiles across healthy forebrain-organoid developmental time points, as well as a patient derived AD organoid time point, allowing us to study brain development at the cellular and molecular levels. In the present study, we identified stage specific differentially hydroxymethylated regions that demonstrated unique acquisition and depletion of 5hmC modifications across development stages. In addition, genes bearing concomitant increases or decreases in both 5hmC and gene expression were enriched in neurobiological processes or early developmental processes respectively. Our AD organoids corroborate both cellular and epigenetic phenotypes previously observed in human AD brains. Importantly, in AD organoids, we identified significant 5hmC alterations at key neurodevelopmental and AD-risk genes, consequently downregulating genes involved in neurodevelopmental and immune response pathways. Collectively our data indicates that, during human fetal neurodevelopment, the precise temporal regulation of 5hmC could modulate key gene expression patterns ensuring that critical neurodevelopmental milestones are achieved. Further, we also demonstrate that premature epigenetic dysregulation of the 5hmC landscape during neuronal development may predispose AD pathogenesis.
2021-04-27 | GSE151818 | GEO
Project description:GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders - Organoid
| PRJEB70618 | ENA
Project description:<p>Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, partly through the activation of 12/15- lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.</p>
2020-11-03 | MTBLS1952 | MetaboLights
Project description:We recently identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental phenotypes, where severely affected probands carried an excess of rare pathogenic variants in the genome compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, but other hits in the genetic background modulate the ultimate phenotypic trajectory. To test this model, we examined the individual contribution of 16p12.1 homologs towards neurodevelopmental, cellular and molecular phenotypes in Drosophila melanogaster and Xenopus laevis. We observed that 16p12.1 homologs affect multiple phenotypic domains, leading to developmental delay, seizure susceptibility, brain size alterations, abnormal neuronal morphology, and cellular proliferation defects. In contrast to genes within CNVs of higher de novo occurrence, such as 16p11.2 deletion, homologs of 16p12.1 genes did not interact with each other, were less connected in a human brain network, and were sensitive to variation in the genetic background. Moreover, 214 “two-hit” models in the fly eye identified additive (47%), suppressive (34.5%), and epistatic (18.5%) interactions between 16p12.1 homologs and 80 homologs of genes carrying “second-hits” in children with the deletion and genes within related neurodevelopmental pathways. In fact, homologs of the intellectual disability-associated “second-hit” gene SETD5 synergistically interacted with homologs of MOSMO, modifying brain and cellular phenotypes and leading to new neuronal defects. Our results provide functional evidence for the “two-hit” model of neurodevelopmental disorders, where multiple 16p12.1 genes sensitize the genome to developmental defects, and complex domain-specific interactions with “second-hit” genes define the final phenotypic manifestation.
2020-05-28 | GSE151330 | GEO