Fate plasticity of interneuron specification
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ABSTRACT:
PROVIDER: PRJNA1167741 | ENA |
REPOSITORIES: ENA
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Project description:The generation of neuronal subtypes in the mammalian central nervous system is driven by competing genetic programs. The medial ganglionic eminence (MGE) gives rise to two major cortical interneuron (cIN) populations, marked by Somatostatin (Sst) and Parvalbumin (Pvalb), which develop on different timelines. The extent to which external signals influence these identities remains poorly understood. Pvalb-positive cINs are particularly important for regulating cortical circuits through strong perisomatic inhibition, yet they have been difficult to model in vitro. Here we investigated the role of the environment in shaping and maintaining Pvalb cINs. We grafted mouse MGE progenitors into a variety of 2D and 3D coculture models, including mouse and human cortical, MGE, and thalamic systems with dissociated cells, organoids, organotypic cultures, and conditioned media. Across models, we observed distinct proportions of Sst- and Pvalb-positive cIN descendants. Strikingly, grafting MGE progenitors into 3D human, but not mouse, corticogenesis models led to efficient, non-autonomous differentiation of Pvalb-positive cINs. This differentiation was characterized by upregulation of Pvalb maturation markers, downregulation of Sst-specific markers, and the formation of perineuronal nets. Furthermore, lineage-traced postmitotic Sst-positive cINs, when grafted, also upregulated Pvalb expression. These results reveal an unexpected level of fate plasticity in MGE-derived cINs, demonstrating that their identities can be dynamically shaped by the surrounding environment.
2024-11-24 | GSE278531 | GEO
Project description:Short- and long-distance extrinsic regulation of interneuron specification and migration.
2022-05-30 | GSE202874 | GEO
Project description:Hnrnpa21 regulates myogenic fate plasticity
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Project description:Combinatorial transcription codes generate the myriad of cell types during development, and thus likely provide crucial insights into directed differentiation of stem cells to a specific cell type. The LIM-complex composed of Isl1 and Lhx3 directs the specification of spinal motor neurons (MNs) in embryos. Here, we report that Isl1-Lhx3, a LIMcomplex-mimicking fusion, induces a signature of MN transcriptome and concomitantly suppresses interneuron differentiation programs, thereby serving as a potent and specific inducer of MNs in stem cells. We show that an equimolar ratio of Isl1 and Lhx3 and the LIM-domain of Lhx3 are crucial for generating MNs without upregulating interneuron genes. These led us to design Isl1-Lhx3, which maintains the desirable 1:1 ratio of Isl1 and Lhx3 and the LIM-domain of Lhx3. Isl1-Lhx3 drives MN differentiation with high specificity and efficiency in the spinal cord and embryonic stem cells, bypassing the need for sonic hedgehog. RNA-seq analysis revealed that Isl1-Lhx3 induces the expression of a battery of MN genes that control various functional aspects of MNs, while suppressing key interneuron genes. Our studies uncover a highly efficient method for directed MN generation and MN gene networks. Our results also demonstrate a general strategy of utilizing embryonic transcription complexes for producing specific cell types from stem cells. Examine the RNA expression profiles of inducible motor neurons-embryonic stem cells (iMN-ESCs) with or without Dox treatment, with biological duplicates.
2012-02-03 | E-GEOD-35510 | biostudies-arrayexpress
Project description:Non-cell-autonomous regulation of interneuron specification mediated by extracellular vesicles
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Project description:Short- and long-distance extrinsic regulation of interneuron specification and migration
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Project description:Epithelial differentiation in the female reproductive tract (FRT) is essential for reproductive health, yet the mechanisms that govern epithelial fate specification remain poorly understood. At birth, FRT epithelium exhibits significant developmental plasticity, allowing differentiation into various epithelial subtypes. However, the regulatory pathways driving these early fate decisions, particularly in the uterus, are largely uncharacterized. Here, we employ neonatal mouse endometrial epithelial organoids and assembloid co-culture models to investigate how intrinsic cellular plasticity and mesenchymal signals influence uterine epithelial differentiation. We demonstrate that uterine epithelium undergoes marked age-dependent changes, shifting from a highly plastic state capable of differentiating into both monolayered and multilayered structures to a more restricted fate as development progresses. Interestingly, parallels between the developmental plasticity of neonatal uterine epithelium and pathological conditions such as endometrial cancer emerged, where similar regulatory mechanisms may be reactivated, driving abnormal epithelial differentiation and tumorigenesis. These findings provide new insights into the regulatory networks that guide early development and highlight how disruptions in these processes can contribute to disease, offering a valuable model for studying both normal uterine development and cancer progression.
2025-01-01 | GSE278635 | GEO
Project description:Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. Regulating cell identity requires gene activation and repression. While master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether unwanted plasticity is actively suppressed by lineage-specific repressors. Here, we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that Prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternate fate master regulators. In line with patient data, PROX1 overexpression in mice blocked initiation and progression of hepatocellular carcinoma and extended survival. Remarkably, Prox1 depletion caused hepatocyte fate loss in vitro, and promoted transdifferentiation of hepatocellular- to cholangio-carcinoma in vivo. Our findings provide mechanistic evidence for PROX1 as a hepatocyte-specific safeguard and support a model where individual cell type-specific repressors actively suppress plasticity throughout life to safeguard lineage choice and prevent disease.
2024-11-11 | PXD053043 | Pride
Project description:RNA-binding proteins (RBPs) are essential for skeletal muscle regeneration and RBP dysfunction causes muscle degeneration and neuromuscular disease (NMD). How the timing of RBP function governs the complex cell fate decisions during muscle regeneration is poorly understood. Here, single cell analysis of skeletal muscle regeneration reveals the timing of NMD-associated RBPs expression in muscle progenitors, including a massive upregulation of Hnrnpa2b1 (A2b1). A2b1 promotes muscle progenitor plasticity by regulating the splicing of RNAs expressed at specific times during the trajectory of muscle differentiation. Using RBP-RNA engagement scoring and machine learning, we accurately predict NMD-associated RBP functionality in directing myogenesis. Together our analysis reveals how A2b1 regulates myogenic plasticity and provides a broadly applicable single cell methodology for examining how RBPs influence complex cell fate trajectories.
2020-06-16 | GSE152467 | GEO
Project description:Cell fate specification of neural stem/progenitor cells (NSCs) is an intricate developmental process that determines neural cell identity. While transcriptional mechanisms undoubtedly affect this process, translational mechanisms are much less understood. Here we show that deficiency of the chromatin remodeler Chromodomain Helicase DNA binding protein 5 (Chd5) causes transcriptional de-repression of multiple ribosomal subunit genes, increases protein synthesis, and expands the activated stem cell pool leading to perturbation of NSC fate. Compromised H3K27me3 in Chd5 deficient NSCs during early cell fate specification underlies the generation of excessive astrocytes at the expense of neurons at later stages of differentiation. Chd5 expression rescues these cell fate defects while simultaneously reestablishing H3K27me3, and inhibition of the H3K27me3-specific demethylase Utx restores appropriate cell fate specification in NSCs lacking Chd5. These findings define a Chd5-Utx-H3K27me3 axis pivotal in ribosome biogenesis and translation during neurogenesis, consistent with compromised CHD5 being implicated in glioma.
2018-08-22 | GSE80583 | GEO