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Single-Cell Transcriptomics Reveals Conserved Regulatory Networks in Human and Mouse Interneuron Development.

ABSTRACT: 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 foetal 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 programs. Moreover, we identified novel candidate transcription regulators for human interneuron differentiation. These findings provide a framework for in vitro modelling of interneuron development and a strategy for potentially enhancing interneuron production from human pluripotent stem cells.

SUBMITTER: Keefe F

PROVIDER: S-EPMC10179417 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Single-Cell Transcriptomics Reveals Conserved Regulatory Networks in Human and Mouse Interneuron Development.

Keefe Francesca F Monzón-Sandoval Jimena J Rosser Anne E AE Webber Caleb C Li Meng M

International journal of molecular sciences 20230501 9

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) o ...[more]

PMID: 37175835

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Project description:Cortical interneurons (cINs) modulate excitatory neuronal activity by providing local inhibition. During fetal development, several cIN subtypes derive from the medial ganglionic eminence (MGE), a transient ventral telencephalic structure. While altered cIN development contributes to neurodevelopmental disorders, the inaccessibility of human fetal brain tissue during development has hampered efforts to define molecular networks controlling this process. Here, we modified protocols for directed differentiation of human embryonic stem cells, obtaining efficient, accelerated production of MGE-like progenitors and MGE-derived cIN subtypes with the expected electrophysiological properties. We defined transcriptome changes accompanying this process and integrated these data with direct transcriptional targets of NKX2-1, a transcription factor controlling MGE specification. This analysis defined NKX2-1-associated genes with enriched expression during MGE specification and cIN differentiation, including known and previously unreported transcription factor targets with likely roles in MGE specification, and other target classes regulating cIN migration and function. NKX2-1-associated peaks were enriched for consensus binding motifs for NKX2-1, LHX, and SOX transcription factors, suggesting roles in coregulating MGE gene expression. Among the NKX2-1 direct target genes with cIN-enriched expression was CHD2, which encodes a chromatin remodeling protein mutated to cause human epilepsies. Accordingly, CHD2 deficiency impaired cIN specification and altered later electrophysiological function, while CHD2 coassociated with NKX2-1 at cis-regulatory elements and was required for their transactivation by NKX2-1 in MGE-like progenitors. This analysis identified several aspects of gene-regulatory networks underlying human MGE specification and suggested mechanisms by which NKX2-1 acts with chromatin remodeling activities to regulate gene expression programs underlying cIN development.

Project description:BackgroundHigh-risk neuroblastoma is a pediatric cancer with still a dismal prognosis, despite multimodal and intensive therapies. Tumor microenvironment represents a key component of the tumor ecosystem the complexity of which has to be accurately understood to define selective targeting opportunities, including immune-based therapies.MethodsWe combined various approaches including single-cell transcriptomics to dissect the tumor microenvironment of both a transgenic mouse neuroblastoma model and a cohort of 10 biopsies from neuroblastoma patients, either at diagnosis or at relapse. Features of related cells were validated by multicolor flow cytometry and functional assays.ResultsWe show that the immune microenvironment of MYCN-driven mouse neuroblastoma is characterized by a low content of T cells, several phenotypes of macrophages and a population of cells expressing signatures of myeloid-derived suppressor cells (MDSCs) that are molecularly distinct from the various macrophage subsets. We document two cancer-associated fibroblasts (CAFs) subsets, one of which corresponding to CAF-S1, known to have immunosuppressive functions. Our data unravel a complex content in myeloid cells in patient tumors and further document a striking correspondence of the microenvironment populations between both mouse and human tumors. We show that mouse intratumor T cells exhibit increased expression of inhibitory receptors at the protein level. Consistently, T cells from patients are characterized by features of exhaustion, expressing inhibitory receptors and showing low expression of effector cytokines. We further functionally demonstrate that MDSCs isolated from mouse neuroblastoma have immunosuppressive properties, impairing the proliferation of T lymphocytes.ConclusionsOur study demonstrates that neuroblastoma tumors have an immunocompromised microenvironment characterized by dysfunctional T cells and accumulation of immunosuppressive cells. Our work provides a new and precious data resource to better understand the neuroblastoma ecosystem and suggest novel therapeutic strategies, targeting both tumor cells and components of the microenvironment.

Dataset Information

Single-Cell Transcriptomics Reveals Conserved Regulatory Networks in Human and Mouse Interneuron Development.

Publications

Single-Cell Transcriptomics Reveals Conserved Regulatory Networks in Human and Mouse Interneuron Development.

Similar Datasets

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