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Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure [miRNA-seq]

ABSTRACT: We investigated microRNA expression in motoneurons by performing small RNA sequencing of fluorescence-activated cell sorting (FACS)-isolated motoneurons labelled with the Hb9:gfp transgenic reporter and Hb9:gfp negative non-motoneurons including spinal interneurons. We find that one microRNA, microRNA-218, is highly enriched and abundantly expressed in motoneurons. Furthermore, we find that miR-218 is transcribed from alternative, motoneuron-specific alternative promoters embedded within the Slit2 and Slit3 genes by performing RNA sequencing of FACS-isolated motoneurons and a dissected embryonic floor plate cells which served as a control. Next, we performed RNA sequencing of FACS-isolated wild type (WT) motoneurons and motoneurons lacking miR-218 expression (218DKO motoneurons), and find that a large set of genes (named 'TARGET218' genes) with predicted miR-218 binding sites are de-repressed in the absence of miR-218 expression. Finally, we examine the expression of TARGET218 genes in other neuronal subpopulations by FACS-isolating V1, V2a, and V3 interneurons expressing Cre-inducible fluorescent reporters and performing RNA sequencing. We find that the TARGET218 network of genes is depleted in wild-type motoneurons versus these interneuron types. Additionally, these genes are expressed at similar levels in 218DKO motoneurons compared with interneuron subtypes, suggesting that this genetic network. Examination of miRNA expression in spinal neuron subpopulations.

ORGANISM(S): Mus musculus

SUBMITTER: Neal Amin

PROVIDER: E-GEOD-75600 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure [RNA-seq]

Project description:We investigated microRNA expression in motoneurons by performing small RNA sequencing of fluorescence-activated cell sorting (FACS)-isolated motoneurons labelled with the Hb9:gfp transgenic reporter and Hb9:gfp negative non-motoneurons including spinal interneurons. We find that one microRNA, microRNA-218, is highly enriched and abundantly expressed in motoneurons. Furthermore, we find that miR-218 is transcribed from alternative, motoneuron-specific alternative promoters embedded within the Slit2 and Slit3 genes by performing RNA sequencing of FACS-isolated motoneurons and a dissected embryonic floor plate cells which served as a control. Next, we performed RNA sequencing of FACS-isolated wild type (WT) motoneurons and motoneurons lacking miR-218 expression (218DKO motoneurons), and find that a large set of genes (named 'TARGET218' genes) with predicted miR-218 binding sites are de-repressed in the absence of miR-218 expression. Finally, we examine the expression of TARGET218 genes in other neuronal subpopulations by FACS-isolating V1, V2a, and V3 interneurons expressing Cre-inducible fluorescent reporters and performing RNA sequencing. We find that the TARGET218 network of genes is depleted in wild-type motoneurons versus these interneuron types. Additionally, these genes are expressed at similar levels in 218DKO motoneurons compared with interneuron subtypes, suggesting that this genetic network. Examination of mRNA expression in spinal progenitor, glial, and neuronal subpopulations.

2015-12-18 | E-GEOD-75599 | biostudies-arrayexpress

Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure [miRNA-seq]

2015-12-18 | GSE75600 | GEO

Loss of motoneuron-specific microRNA-218 causes systemic neuromuscular failure [RNA-seq]

2015-12-18 | GSE75599 | GEO

A hidden threshold in motor neuron gene networks for survival revealed by modulation of miR-218 dose

Project description:miRNAs are post-transcriptional repressors with wide variation in cellular abundance across cell types and disease states. Yet, the transcriptomic and biological impact of altering miRNA levels (rather than binary gain or loss) has not been systematically investigated. By genetic combination, we generated an allelic series of mice expressing varying levels of miR-218, a motor neuron-specific miRNA associated with amyotrophic lateral sclerosis (ALS). Modulation of miR-218 dose causes threshold-like neuromuscular synaptogenesis and mouse viability phenotypes and revealed heterogenous dose-response curves of target mRNA repression. A dose-response network analyses unmasked a specific regulon exhibiting an inflection point in repression concomitant with the emergence of motor phenotypes. Furthermore, we find that miR-218 indirectly activates a coherent peripheral neuronal genetic signature and that the magnitude of miR-218 mediated effects varies in distinct motor subpopulations. This work reveals miRNA dose as a potent, non-linear modulator of in vivo mRNA target selection, suggesting how cellular dysfunction might abruptly arise when miRNA levels fall below a critical threshold. For the data uploaded here, motor neurons carrying an Hb9:gfp reporter were FACS isolated based upon GFP expression and used for either bulk or single cell RNA sequencing (10x genomics). Motor neurons were either mouse embryonic stem cell derived motor neurons (ESMNs) or mouse motor neurons from developmental stage E12. ESMN samples carry unique mutations of the miR-218-2 promoter of distinct sizes, or are wild type. E12 motor neurons carry combinations of mutations to either miR-218-1 or miR-218-2 or the promoter for miR-218-2. For single cell RNA sequencing, we have WT and miR-218 double knockout (DKO) motor neurons in duplicate. We also sequenced 4 samples of dorsal root ganglia from E12 mice (DRG1-4).

2021-08-27 | E-MTAB-10571 | biostudies-arrayexpress

MicroRNA-218 instructs proper assembly of hippocampal networks

Project description:The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. Post-transcriptional regulation of gene expression by microRNAs (miRNAs) is a key aspect of this program. Indeed, deletion of neuron-enriched miRNAs induces strong developmental phenotypes, and miRNA levels are altered in patients with neurodevelopmental disorders. However, the mechanisms used by miRNAs to instruct brain development remain largely unexplored. Here, we identified miR-218 as a critical regulator of hippocampal assembly. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons (PNs) and GABAergic inhibitory interneurons (INs). Early life inhibition of miR-218 results in an adult brain with a predisposition to seizures. Changes in gene expression in the absence of miR-218 suggest that network assembly is impaired. Indeed, we find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Conditional knockout of miR-218 in INs, but not PNs, is sufficient to recapitulate long-term instability. Finally, de-repressing Kif21b and Syt13, two miR-218 targets, phenocopies the effects on early synchronous network activity induced by miR-218 inhibition. Taken together, the data suggest that miR-218 orchestrates formative events in PNs and INs to produce stable networks.

2023-10-15 | GSE241245 | GEO

The involvement of motor neuron specific miR-218 in human ALS

Project description:Motor-neuron specific microRNA-218 (miR-218) was recently put in the spotlight because of its striking roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic lateral sclerosis (ALS) motor neurons miR-218 is downregulated and its mRNA targets are reciprocally upregulated (de-repressed). We further identify the potassium channel Kv10.1 as a new miR-218 direct target that controls neuronal activity. In addition, we screened thousands of ALS genomes and identified six rare variants in the human miR-218-2 sequence. Intriguingly, miR-218 gene variants fail to regulate neuron activity, suggesting the importance of this small endogenous RNA for neuronal robustness. The underlying mechanisms involve inhibition of miR-218 biogenesis and reduced processing by DICER. Therefore, miR-218 activity uncovers a previously unappreciated facet of motor neuron specificity that may be particularly susceptible to failure in human ALS, contributes to a view of ALS as a disease with a prominent RNA component and suggests that miR-218 is a potential therapeutic target for motor neuron disease.

2019-08-28 | GSE136409 | GEO

microRNA-218 modulates gene expression in fibroblast-like synovial cells in rheumatoid arthritis

Project description:Objective: Fibroblast-like synovial cells (FLS) have multilineage differentiation potential including osteoblasts. We aimed to investigate the role of microRNAs during the osteogenic differentiation of rheumatoid arthritis (RA)-FLS. Methods: MicroRNA(miRNA) array analysis was performed to investigate the differentially expressed miRNAs during the osteogenic differentiation. Expression of miR-218-5p (miR-218) during the osteogenic differentiation was determined by quantitative real-time PCR. Transfection with miR-218 precursor and inhibitor were used to confirm the targets of miR-218 and to analyse the ability of miR-218 to induce osteogenic differentiation. Results: The miRNA array revealed that 12 miRNAs were up-regulated and 24 miRNAs were down-regulated after osteogenic differentiation. We observed that miR-218 rose in the early phase of osteogenic differentiation and then decreased. Micro array analysis revealed the mir-218 modulate the expression of ROBO1 in RA-FLS. The induction of miR-218 in RA-FLS decreased ROBO1 expression, and promoted osteogenic differentiation.

2018-03-26 | GSE111946 | GEO

Defining the nature of human pluripotent stem cell-derived interneurons via single cell analysis

Project description:We applied single nuclei and single cell transcriptomics methods to model interneuron development with interneurons derived from human PSCs. We find that PSC-derived interneurons capture stages of development prior to mid gestation, but only represent a minority of potential subtypes that are found in the brain. Comparison of these interneurons to those found in the adult brain highlighted decreased expression of synapse-related genes, reflective of their electrophysiological immaturity. Together, these analyses provide a full characterization of PSC-derived interneurons.

2021-07-15 | GSE180132 | GEO

Molecular blueprints for spinal circuit modules controlling locomotor speed

Project description:The flexibility of motor actions is ingrained in the diversity of neurons and how they are organized into functional circuit modules, yet our knowledge of the molecular underpinning of motor circuit modularity remains limited. Locomotion is a motor behavior characterized by sudden changes in speed and strength enabled by the coordinated recruitment of different motoneuron subtypes. Here we use adult zebrafish to link the molecular diversity of motoneurons and the rhythm-generating V2a interneurons with their modular circuit organization that is responsible for changes in locomotor speed. We show that the molecular diversity of motoneurons and V2a interneurons reflects their functional segregation into slow, intermediate or fast subtypes. Furthermore, we reveal shared molecular signatures between V2a interneurons and motoneurons of the three speed circuit modules. Overall, by characterizing how the molecular diversity of motoneurons and V2a interneurons relates to their function, connectivity and behavior, our study provides important insights not only into the molecular mechanisms for neuronal and circuit diversity for locomotor flexibility but also for charting circuits for motor actions in general.

2023-09-29 | GSE243993 | GEO

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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