Single cell RNA-seq analysis of astrocyte to neuron reprograming [Patch-seq1]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE173977 | GEO | 2021/07/20
REPOSITORIES: GEO
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Project description:Astrocytes, the most abundant cells in the central nervous system, promote synapse formation and help refine neural connectivity. Although they are allocated to spatially distinct regional domains during development, it is unknown whether region-restricted astrocytes are functionally heterogeneous. Here we show that postnatal spinal cord astrocytes express several region-specific genes, and that ventral astrocyte-encoded Semaphorin3a (Sema3a) is required for proper motor neuron and sensory neuron circuit organization. Loss of astrocyte-encoded Sema3a led to dysregulated α−motor neuron axon initial segment orientation, markedly abnormal synaptic inputs, and selective death of α−but not of adjacent γ−motor neurons. Additionally, a subset of TrkA+ sensory afferents projected to ectopic ventral positions. These findings demonstrate that stable maintenance of a positional cue by developing astrocytes influences multiple aspects of sensorimotor circuit formation. More generally, they suggest that regional astrocyte heterogeneity may help to coordinate postnatal neural circuit refinement. 12 total samples consisting of three biological replicates each of flow sorted postnatal day 7 dorsal spinal cord astrocytes, ventral spinal cord astrocytes, dorsal SC non astrocytes, and ventral SC non astrocytes
2014-05-02 | E-GEOD-55054 | biostudies-arrayexpress
Project description:Single cell RNA-seq analysis of astrocyte to neuron reprograming [Patch-seq1]
| PRJNA727800 | ENA
Project description:Purpose of the study is to compare the transcriptional profiles of reprogrammed neurons from spinal cord-derived astrocytes, analyzed after electrophysiological recordings, and control astroctes.
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Project description:Diversified neurons are essential for sensorimotor function, but whether astrocytes become specialized to optimize circuit performance remains unclear. Large fast α-motor neurons (FαMNs) of spinal cord innervate fast-twitch muscles that generate peak strength. We report that ventral horn astrocytes express the inward rectifying K+ channel Kir4.1 (aka, Kcnj10) around MNs in a VGLUT1-dependent manner. Loss-of astrocyte-encoded Kir4.1 selectively altered FαMN size, function and led to reduced peak strength. Overexpression of Kir4.1 in astrocytes was sufficient to increase MN size through activation of the PI3K/mTOR/pS6 pathway. Kir4.1 was downregulated cell-autonomously in astrocytes derived from amyotrophic lateral sclerosis (ALS) patients with SOD1 mutation. However, astrocyte Kir4.1 was dispensable for FαMN survival even in the mutant SOD1 background. These findings show that astrocyte Kir4.1 is essential for maintenance of peak strength and suggest that Kir4.1 downregulation uncouples symptoms of muscle weakness from MN cell death in ALS.
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Project description:Single-nuclei Assay for Transposase-Accessible Chromatin with sequencing (snATACseq) was applied to examine chromatin landscape changes and transcriptional regulator (TR) DNA motif accessibility in reactive astrocytes following traumatic spinal cord injury (SCI). Astrocyte nuclei were isolated from the spinal cord of wild type mice and mice with astrocyte-specific conditional gene deletion (cKO) of test-case TRs, SMARCA4 (Smarca4-astro-cKO) or STAT3 knockout (Stat3-astro-cKO). Comparison of differential chromatin accessibility revealed substantial remodeling during astrocyte reactivity, with more chromatin opening than closing. Marked alterations in access to SCI reactivity-associated TR motifs were also detected.
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Project description:Spinal cord injury (SCI) is a common but devastating trauma of the central nerve system. In this study, we reprogrammed cultured spinal-cord reactive astrocytes into neurons by Neurod1 expression. The mechanism of programmed conversion from astrocytes to neurons has not been clarified yet. Thus, we used label-free proteomics to identify differentially expressed proteins in Neurod1 over-expressed astrocytes and control group. A total of 1952 proteins were identified, including 92 significantly changed proteins. Among these proteins, 8 proteins were identified as candidates involving in the process of the reprogramming, based on their biological function and fold change in the bioinformatic analysis. Our study revealed that that Neurod1 can directly reprogram cultured spinal-cord reactive astrocytes into neurons, and several proteins that could play a significant role during the neuronal reprogramming were discovered.
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Project description:Profiling of transcriptional changes in rat astrocytes when co-cultured with neurons: comparison of astrocytes cultured alone with astrocytes co-cultured with mouse hippocampal neurons. Co-cultured astrocytes are isolated using cold jet, a novel tool for these neuron-glia cultures. Over the last decade, the importance of astrocyte-neuron communication in neuronal development and synaptic plasticity has become increasingly clear. Since neuron-astrocyte interactions represent highly dynamic and reciprocal processes, we hypothesized that at least part of the involved astrocyte genes may be regulated as a consequence of their interactions with maturing neurons. In order to identify such neuron-induced astrocyte genes in vitro, we tested the effectiveness of the ‘cold jet’, a new method for separation of neurons from co-cultured astrocytes. The cold jet method is performed under ice-cold conditions and avoids protease-mediated isolation of astrocytes or time-consuming centrifugation, yielding intact astrocyte mRNA with approximately 90% of neuronal RNA removed. Using this method, we executed genome-wide profiling in which RNA derived from astrocyte-only cultures was compared with astrocyte RNA derived from differentiating neuron-astrocyte co-cultures. Data analysis revealed changes in expression of a large number of mRNAs and biological processes, including novel findings. Thus, cold jet is an efficient method to separate astrocytes from neurons in co-culture, and in this study reveals that neurons induce robust gene-expression changes in co-cultured astrocytes.
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Project description:Astrocytes and neurons coexist and interact in the CNS1,2. Given that many signaling and pathological events are protein-driven, identifying astrocyte and neuron proteomes is essential for elucidating the complex protein networks that dictate their respective contributions to physiology and disease. Here, we used cell- and subcompartment-specific proximity-dependent biotinylation3 to study the proteomes of striatal astrocytes and medium spiny neurons (MSNs) in vivo. We evaluated cytosolic and plasma membrane compartments for astrocytes and MSNs, revealing how these cells differ at the protein level and in their core signaling machinery. We assessed subcellular compartments of astrocytes including end feet and processes to reveal the molecular basis of essential astrocyte signaling and homeostatic functions. Unexpectedly, SAPAP3 proteins (gene; Dlgap3) associated with obsessive compulsive disorder (OCD) and repetitive behaviors4-11 were detected at equivalent levels in striatal astrocyte and MSN plasma membrane and cytosolic compartments. Astrocytic expression was confirmed by RNA-seq, fluorescence in situ hybridization and immunohistochemistry. Furthermore, genetic rescue experiments combined with behavioral analyses and proteomics in a mouse model4 of OCD lacking SAPAP3 revealed contributions of SAPAP3 in astrocytes and MSNs to repetitive and anxiety-related OCD behaviors. Our data define how astrocytes and neurons differ at the protein level and in their major signaling pathways, how astrocyte proteomes vary between physiological subcompartments, and how specific astrocyte and neuronal molecular mechanisms contribute to a psychiatric disease. Targeting both astrocytes and neurons together is likely to be therapeutically effective in complex CNS disorders.
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Project description:We isolated and gene expression profiled distinct astrocyte subtypes from three central nervous system regions: forebrain, hindbrain, and spinal cord, using a FACS-based protocol. Cell surface expression of Glast/Slc1a3 (G) and Acsa-2/Atp1b2 (A) was used to distinguish subpopulations of astrocytes. Furthermore, we assessed the transcriptome of cultured primary neonatal astrocytes. The local brain environment proved key in establishing different transcriptional programs in astrocyte subtypes. Functional differences between subtypes were also apparent in experimental autoimmune encephalomyelitics (EAE) mice, where these astrocyte subtypes showed distinct responses. While gene expression signatures associated with blood-brain-barrier maintenance were lost during EAE, signatures contributing to neuroinflammation were increased specifically in astrocytes in the spinal cord.
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