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All-defined NGN2 neuron protocol reveals multifaceted signatures of neuronal maturation [scRNA-seq]

ABSTRACT: Direct conversion of iPSCs into neurons by NGN2 over-expression is a popular method for disease modeling. Here we report a standardized method to generate functional excitatory cortical neurons using clonal, targeted engineered iPSC lines and defined reagents. We demonstrate that our protocol generates consistent excitatory cortical neurons at scale. These cultures can be maintained healthily for at least 150 days and expresses the majority of the GWAS genes found in autism, Parkinson’s disease, and Alzheimer’s disease. Comprehensive temporal omics, functional, and morphological profiling demonstrated continued progression of neuronal maturation. Deep functional characterization through transcriptomic, imaging, and functional assays revealed the coordinated action of multiple pathways in neuronal maturation. Our method and profiling data can serve as reference for developing human in vitro neuronal models for disease modeling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244370 | GEO | 2024/09/15

REPOSITORIES: GEO

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All-defined NGN2 neuron protocol reveals multifaceted signatures of neuronal maturation [bulk_media]

Project description:Direct conversion of iPSCs into neurons by NGN2 over-expression is a popular method for disease modeling. Here we report a standardized method to generate functional excitatory cortical neurons using clonal, targeted engineered iPSC lines and defined reagents. We demonstrate that our protocol generates consistent excitatory cortical neurons at scale. These cultures can be maintained healthily for at least 150 days and expresses the majority of the GWAS genes found in autism, Parkinson’s disease, and Alzheimer’s disease. Comprehensive temporal omics, functional, and morphological profiling demonstrated continued progression of neuronal maturation. Deep functional characterization through transcriptomic, imaging, and functional assays revealed the coordinated action of multiple pathways in neuronal maturation. Our method and profiling data can serve as reference for developing human in vitro neuronal models for disease modeling.

2024-09-15 | GSE244368 | GEO

All-defined NGN2 neuron protocol reveals multifaceted signatures of neuronal maturation [bulk timecourse]

2024-09-15 | GSE244369 | GEO

Transcription profiling of mouse wild type vs Dnmt1 hypomethylated forebrain

Project description:DNA methylation is a major epigenetic factor regulating genome reprogramming, cell differentiation, developmental gene expression. To understand the role DNA methylation in CNS neurons, we generated conditional Dnmt1 mutant mice that possess ~90% hypomethylated cortical and hippocampal cells in the dorsal forebrain from E13.5 on. The mutant mice were viable with a normal lifespan, but displayed severe neuronal cell death between E14.5 to 3-weeks postnatally. Accompanied with the striking cortical and hippocampal degeneration, adult mutant mice exhibited neurobehavioral defects in learning and memory in adulthood. Unexpectedly, a fraction of Dnmt1-/- cortical neurons survived through postnatal development, so that the residual cortex in mutant mice contained 20-30% of hypomethylated neurons throughout the life. Hypomethylated excitatory neurons exhibited multiple defects in postnatal maturation including abnormal dendritic arborization and impaired neuronal excitability. The mutant phenotypes are coupled with deregulation of those genes involved in neuronal layer-specification, cell death, and the function of ion channels. Our results suggest that DNA methylation, through its role in modulating neuronal gene expression, plays multiple roles in regulating cell survival, neuronal migration and maturation in the CNS. Experiment Overall Design: We compared gene expression patterns in Wildtype and DNA methylation deficient (Emx1-cre; Dnmt1 mutant) mouse dorsal cortex. We performed 3 replicates using different each individual mouse strain. The Sample GSM350992 table is the average log ratio for the 3 replicatesArrays were performed in triplicate.

2009-12-18 | E-GEOD-14216 | biostudies-arrayexpress

RNA-seq investigating the influence of astrocytes on developing cortical neurons

Project description:Astrocytes are implicated in neuronal development, particularly excitatory synaptogenesis, but their genome-wide impact is unclear. Using cell-type specific RNA-seq we show that cortical astrocytes induce widespread transcriptomic changes in developing cortical neurons. Rat cortical neurons were maintained in the presence or absence of mouse astrocytes, RNA-seq performed, and mixed-species RNA-seq reads sorted according to species. Cultures were also treated with TTX to abolish neuronal firing activity, to investigate the effects of the presence or absence activity-dependent signalling.

2024-05-14 | E-MTAB-14070 | biostudies-arrayexpress

ChIP-seq investigating the influence of astrocytes on the epigenetic landscape of developing cortical neurons

Project description:Astrocytes are implicated in neuronal development, particularly excitatory synaptogenesis, but their genome-wide impact is unclear. Using cell-type specific ChIP-seq we show that cortical astrocytes induce widespread changes in developing cortical neurons in histone marks associated with active open chromatin and repressed/condensed chromatin. Rat cortical neurons were maintained in the presence or absence of mouse astrocytes, ChIP-seq performed, and mixed-species ChIP-seq reads sorted according to species.

2024-05-16 | E-MTAB-14081 | biostudies-arrayexpress

Ngn2 induces diverse neuronal lineages from human pluripotency

Project description:Human neurons engineered from induced pluripotent stem cells (iPSCs) through Neurogenin 2 (Ngn2) overexpression are widely used to study neuronal differentiation mechanisms and to model neurological diseases. However, the differentiation paths and heterogeneity of emerged neurons have not been fully explored. Here we used single-cell transcriptomics to dissect the cell states that emerge during Ngn2 overexpression across a time course from pluripotency to neuron functional maturation. We find a substantial molecular heterogeneity in the neuron types generated, with at least two populations that express genes associated with neurons of the peripheral nervous system. Neuron heterogeneity is observed across multiple iPSC clones and lines from different individuals. We find that neuron fate acquisition is sensitive to Ngn2 expression level and the duration of Ngn2 forced expression. Our data reveals that Ngn2 dosage can regulate neuron fate acquisition, and that Ngn2-iN heterogeneity can confound results that are sensitive to neuron type.

2021-08-05 | E-MTAB-10632 | biostudies-arrayexpress

Fully defined NGN2 neuron protocol reveals diverse signatures of neuronal maturation

Project description:This bulk RNAseq dataset is part of a dataset described in the manuscript titled "Fully defined NGN2 neuron protocol reveals diverse signatures of neuronal maturation". This dataset includes NPC derived neurons using a wild type iPSC line, and was used to validate a MS-117 maturation score which attempt to establish a socre system to assess neuronal maturation with iPSCs derived neurons.

2024-09-13 | GSE266359 | GEO

WT vs Hypomethylated Forebrain Gene Expression

2009-12-12 | GSE14216 | GEO

Individual Human Cortical Progenitors Can Produce Excitatory and Inhibitory Neurons

Project description:The cerebral cortex is a cellularly-complex structure comprised of a rich diversity of neuronal and glial cell types. Cortical neurons can be broadly categorized into two classes—glutamatergic excitatory neurons and GABAergic inhibitory interneurons. Previous developmental studies in rodents have led to the prevailing model that while excitatory neurons are born from progenitors located in the cortex, cortical interneurons are born from a separate population of progenitors located outside of the developing cortex in the ganglionic eminences1-5. However, the developmental potential of human cortical progenitors has not been thoroughly explored. Here we show that in addition to excitatory neurons and glia, human cortical progenitors are also capable of producing GABAergic neurons with the transcriptional characteristics and morphologies of cortical interneurons. By developing a cellular barcoding tool called “ScRNAseq-compatible Tracer for Identifying Clonal Relationships” (STICR), we were able to perform clonal lineage tracing of 1912 primary human cortical progenitors from six specimens and capture both the transcriptional identities and clonal relationships of their resulting progeny. A subpopulation of cortically-born GABAergic neurons were transcriptionally similar to cortical interneurons born from the caudal ganglionic eminence and these cells were frequently related to excitatory neurons and glia. Thus, our results demonstrate that individual human cortical progenitors can generate both excitatory neurons and cortical interneurons, providing a new framework for understanding the origins of neuronal diversity in the human cortex.

2021-11-06 | GSE187875 | GEO

Single cell analysis of iPSC-derived cortical organoids in biofunctionalized gelatin hydrogels

Project description:Human neural organoid models have become an important tool for studying neurobiology. In this work, we compared Matrigel to an N-cadherin peptide-functionalized gelatin methacryloyl hydrogel (termed GelMA-Cad) for culturing cortical neural organoids. Specifically, we compare five materials: (1) Matrigel, (2) GelMA-Cad with high crosslinker (HC), (3) GelMA-Cad with low crosslinker (LC), (4) GelMA HC and (5) GelMA LC. We determined that both mechanical properties and peptide presentation can tune cell fate and diversity in gelatin-based matrices during differentiation. Of particular note, cortical organoids cultured in GelMA-Cad produce higher numbers of neurogenic and ciliated radial glia and upper-layer excitatory neurons—an important population for modeling neurodegenerative disease—compared to GelMA and Matrigel controls.

2024-02-28 | E-MTAB-13828 | biostudies-arrayexpress

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