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:neurodevelopmental disorders

| PRJNA1453608 | ENA

Phenotypic Screening of human iPSC-Derived Neurons identifies Thienopyridone as a Neuritogenic Small Molecule

Project description:Human induced pluripotent stem cell (iPSC)-derived neurons provide a platform for modeling a wide range of brain disorders. Among disease-relevant cellular phenotypes, impaired neurite outgrowth has emerged as a robust and quantifiable indicator that reflects core aspects of neurodevelopmental and neurodegenerative disease pathophysiology. In this study, we performed a high-throughput phenotypic chemical screen of over 21,000 small molecules to identify compounds that enhance neurite outgrowth in iPSC-derived cortical neurons.By iterative validation using disease-specific and control iPSC-derived neuronal lines, we identified three bioactive compounds that were sharing a common indazole scaffold. Two hit compounds were further validated in a human neural organoid model, where they proliferated neural stem cells by reproducing the neurite-promoting effect. Transcriptomic profiling revealed activation of signaling pathways associated with neurotrophic stimulation. These findings identified a novel scaffold for a neurogenic compound, suggesting the potential of this compound as a therapeutic strategy for brain disorders and for promoting neural regeneration.

2026-03-19 | GSE308370 | GEO

Neuroligin-3 R451C Induces Gain-of-Function Gene Expression in Astroglia in an Astroglia-Enriched Brain Organoid Model

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

5-hydroxymethylcytosine is Dynamically Regulated During Forebrain Organoid Development and Prematurely Altered in Forebrain Organoids of Alzheimer’s Disease Patients

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:chinese with neurodevelopmental disorders

| PRJNA1028277 | ENA

Project description:Genetics of Neurodevelopmental disorders

| PRJNA1169516 | ENA

GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders - Organoid

Project description:GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders - Organoid

| PRJEB70618 | ENA