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Assessment of chromatin state changes during human cortical interneuron development

ABSTRACT: We have used our protocol for generating cortical interneurons from human embryonic stem cells to study chromatin state changes during cortical interneuron development. This allows for the identification of cis-regulatory elements and transcription factors which play important roles in this process. Samples were collected at day 0 (hESCs), day 15 (ventral telencephalic patterned medial ganglionic eminence-like (MGE) progenitors), day 35 (immature interneurons), and day 60 (mature interneurons). Day 15 dorsal telencephalic cortical-like neural progenitors were also obtained by using a dual Smad inhibition protocol for comparison with ventral telencephalic MGE-like progenitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239400 | GEO | 2024/04/18

REPOSITORIES: GEO

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Assessment of gene expression changes during human cortical interneuron development

Project description:We have used our protocol for generating cortical interneurons from human embryonic stem cells (hESCs) to study gene expression changes during this process, to identify regulatory networks critical to cortical interneuron development. Samples were collected at day 0 (hESCs), day 15 (ventral telencephalic patterned medial ganglionic eminence-like progenitors), day 35 (immature interneurons), and day 60 (mature interneurons).

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Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development

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Project description:Organoid techniques provide unique platforms to model brain development and neurological disorders. While organoids recapitulating corticogenesis were established, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, remains to be developed. Here, we describe a system to generate MGE or cortex-specific organoids from human pluripotent stem cells. These organoids recapitulate the developments of MGE and cortex domains respectively. Population and single-cell transcriptomic profiling revealed transcriptional dynamics and lineage productions during MGE and cortical organoids development. Chromatin accessibility landscapes were found to be involved in this process. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, we applied fusion organoids as a model to investigate human interneuron migration. Together, our study provides a new platform for generating domain-specific brain organoids, for modeling human interneuron migration, and offers deeper insight into molecular dynamics during human brain development.

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Project description:Inhibitory GABAergic interneurons originate in the embryonic medial ganglionic eminence (MGE) and control network activity in the neocortex. Dysfunction of these cells is believed to lead to runaway excitation underlying seizure-based neurological disorders such as epilepsy, autism and schizophrenia. Despite their importance in heath and disease, our knowledge about the development of this diverse neuronal population remains incomplete. Here we conducted single cell RNA sequencing (scRNA-seq) of human fetal MGE from 10 to 15 weeks post conception. These MGE tissues are composed of largely cycling progenitors and immature post-mitotic interneurons with characteristic regional marker expression. Analysis of integrated human and mouse MGE data revealed species conserved transcriptomic profiles and regulatory program. Moreover, we identified novel candidate transcription regulators for human interneuron differentiation. These findings provide a framework for in vitro modelling of interneuron development and strategy for potentially enhance interneurons production from human pluripotent stem cells.

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MicroArray Gene Expression Profiling of NKX2.1-GFP+ MGE-like Interneuron Precursors Derived from Human Embryonic Stem Cells

Project description:Human embryonic stem cells with a GFP reporter knock-in into the NKX2.1 locus were differentiated and purified by FACS sorting for global gene expression analysis. Directed differentiation from human pluripotent stem cells (hPSCs) has seen significant progress in recent years. Most differentiated populations, however, exhibit immature properties of an early embryonic stage, raising concerns about their ability to model and treat disease. Here, we report the directed differentiation of hPSCs into medial ganglionic eminence (MGE)-like progenitors and their maturation into forebrain type interneurons. We find that early stage progenitors progress via a radial glial-like stem cell enriched in the human fetal brain. Both in vitro and post-transplantation into the rodent cortex, the MGE-like cells develop into GABAergic interneuron subtypes with mature physiological properties along a prolonged intrinsic timeline of up to seven months, mimicking endogenous human neural development. MGE-derived cortical interneuron deficiencies are implicated in a broad range of neurodevelopmental and degenerative disorders, highlighting the importance of these results for modeling human neural development and disease. Human embryonic stem cells with a GFP reporter knock-in into the NKX2.1 locus were differentiated for 20, 35, and 55 days in vitro and GFP+ cells were purified by FACS sorting. Total RNA was prepared from each timepoint and compared to undifferentiated human embryonic stem cells. hESC = one sample and three technical replicates. D20 = three independent samples. D35 = one sample and two technical replicates. D55 = one sample and one technical replicate.

2013-05-03 | E-GEOD-45660 | biostudies-arrayexpress

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