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Astrocyte-encoded positional cues maintain sensorimotor circuit integrity

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE55054 | GEO | 2014/05/02

SECONDARY ACCESSION(S): PRJNA238347

REPOSITORIES: GEO

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Astrocyte-encoded positional cues maintain sensorimotor circuit integrity

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

Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS

Project description:Background: Astrocytes regulate neuronal function, synaptic formation and maintenance partly through secreted extracellular vesicles (EVs). In amyotrophic lateral sclerosis (ALS) astrocytes display a toxic phenotype that contributes to motor neuron (MN) degeneration. Methods: We used human induced astrocytes (iAstrocytes) from 3 ALS patients carrying C9orf72 mutations and 3 non-affected donors to investigate the role of astrocyte-derived EVs (ADEVs) in ALS astrocyte toxicity. ADEVs were isolated from iAstrocyte conditioned medium via ultracentrifugation and resuspended in fresh astrocyte medium before testing ADEV impact on HB9-GFP+ mouse motor neurons (Hb9-GFP+ MN). We used post-mortem brain and spinal cord tissue from 3 sporadic ALS and 3 non-ALS cases for PCR analysis. Findings: We report that EV formation and miRNA cargo are dysregulated in C9ORF72-ALS iAstrocytes and this affects neurite network maintenance and MN survival in vitro. In particular, we have identified downregulation of miR-494-3p, a negative regulator of semaphorin 3A (SEMA3A). We show here that by restoring miR-494-3p levels through expression of an engineered miRNA mimic we can downregulate Sema3A levels in MNs and increases MN survival in vitro. Consistently, we also report lower levels of mir-494-3p and higher levels of SEMA3A in cortico-spinal tract tissue isolated from sporadic ALS donors, thus demonstrating the pathological importance of this pathway in MNs and its therapeutic potential. Interpretation: ALS ADEVs and their miRNA cargo are involved in MN death in ALS and we have identified miR-494-3p as a potential therapeutic target.

2019-01-08 | GSE122640 | GEO

Rapid clearance of PcG histone modifications from Hox genes anticipates motor neuron differentiation: ChIP-chip

Project description:[original Title] Rapid and synchronous clearance of PcG histone modifications from Hox genes anticipates motor neuron differentiation. Hox genes are expressed in patterns that are spatially and temporally collinear with their chromosomal organization. This feature is an evolutionarily conserved hallmark of embryonic development, and in vertebrates it is critical, among others, for the specification of motor neuron subtypes and the wiring of sensory-motor circuits. We show here that the differentiation of motor neurons from stem cells is accompanied by a synchronous, domain-wide clearance of M-bM-^@M-^\repressiveM-bM-^@M-^] Polycomb (PcG)-dependent histone methylation from Hox gene chromatin domains. These findings argue against the idea, advanced recently, that the collinear dynamics of Hox gene expression invariably reflects the progressive clearance of repressive chromatin modifications. The rapid establishment of stable chromatin domains in response to a transient patterning signal likely serves as a molecular correlate of enduring rostro-caudal neural identity, which underlies the specification of postmitotic motor neuron subtype diversity and neuronal circuit assembly. The differentiation of ventral motor neurons is induced by treating embryonic stem cell cultures with retinoic acid and hedgehog agonist. Here, ChIP-chip using a custom Agilent array is used to profile the occupancy of H3K27me3, H3K4me3, and H3K79me2 at various defined stages during the differentiation process.

2013-07-04 | E-GEOD-19447 | biostudies-arrayexpress

Kir4.1-dependent astrocyte-fast motor neuron interactions are required for peak strength

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.

2018-05-01 | GSE111148 | GEO

FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms

Project description:Non-neuronal cells, including astrocytes, play a crucial role in the selective motor neuron pathology in amyotrophic lateral sclerosis (ALS). How astrocytes exactly contribute to the disease is not fully elucidated. Therefore, we characterised human induced pluripotent stem cell (hiPSC)-derived astrocytes from FUS-ALS patients, and incorporated these astrocytes into a human motor unit model to investigate the astrocytic effect on hiPSC-derived motor neuron network and neuromuscular junctions (NMJs). We observed a dysregulation of astrocyte homeostasis, which resulted in a FUS-ALS-mediated increase in reactivity and secretion of pro-inflammatory cytokines. Upon coculture with motor neurons and myotubes, we detected a cytotoxic effect on motor neuron-neurite morphology and outgrowth, as well as on NMJ formation and functionality, which was improved or fully rescued by isogenic control astrocytes. We conclude that mutant astrocytes have both a gain-of-toxicity and loss-of-support function in ALS, ultimately contributing to the disruption of motor neuron homeostasis, intercellular networks and NMJs.

2023-01-19 | GSE196219 | GEO

Perturbations of the proteome in primary astrocytes from the hSOD1(G93A) ALS mouse model

Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose pathophysiology is largely unknown. Despite motor neuron death is recognized as the key event in ALS, astrocytes dysfunctionalities and neuroinflammation were demonstrated to accompany and probably even drive motor neuron loss. Nevertheless, the mechanisms priming astrocyte failure and hyperactivation are still obscure. In this work, altered pathways in ALS astrocytes were unveiled by investigating the proteomic profile of primary spinal-cord astrocytes derived from transgenic ALS mouse model overexpressing the human (h)SOD1(G93A) protein, in comparison with the transgenic counterpart expressing hSOD1(WT) protein. In this research, we showed that hSOD1(G93A) astrocytes present a profound alterations in the expression of proteins involved in proteostasis and glutathione metabolism.

2022-02-17 | PXD026576 | Pride

Embryonic stem cell-derived brainstem and spinal astrocyte-like cells develop a neurotoxic phenotype in vitro following clinically relevant pro-inflammatory stimulation

Project description:Traumatic axonal injury (TAI) in the brainstem carries a particularly poor prognosis. Although the role of neuroinflammation in this process is incompletely characterized, astrogliosis has been shown to coincide with TAI. Moreover, astrogliotic forebrain astrocytes were recently shown to confer a toxic effect on neurons. We sought to assess if ventral brainstem- or rostroventral spinal astrocytes exert similar effects on motor neurons in vitro. We derived brainstem/rostroventral spinal astrocyte-like cells (ES-astrocytes) and motor neurons using directed differentiation of embryonic stem cells (ES). ES-astrocyte identity was assessed using RNA-sequencing, immunocytochemistry, and comparison with primary subventricular zone-astrocytes. We activated the ES-astrocytes using the neurotoxicity-eliciting cytokines interleukin- (IL-) 1α and tumor necrosis factor-(TNF-)α. In co-cultures with reactive ES-astrocytes and motor neurons, we demonstrated neurotoxic ES-astrocyte activity, similarly to what has previously been shown for other central nervous system (CNS) regions. When exposed to IL-1β and IL-6, two neuroinflammatory cytokines found in the cerebrospinal fluid and serum proteome following severe traumatic brain injury (TBI), ES-astrocytes exerted similar effects on motor neurons. This demonstrates that ventral brainstem and rostroventral spinal cord astrocytes can exert neurotoxic effects in vitro. This highlights the importance of neuroinflammation as a secondary injury mechanism following neurotrauma, and presents a possible treatment avenue to improve neuronal survival in particularly vulnerable CNS regions following TAI.

2023-04-02 | GSE213804 | GEO

Loss of TDP-43 in astrocytes leads to motor deficits by triggering A1-like reactive phenotype and tri-glial dysfunctions

Project description:The majority of patients with amyotrophic lateral sclerosis (ALS) have abnormal TDP-43 aggregates in the nucleus and/or cytosol of their surviving neurons and glia. Although accumulating evidence indicates that astroglial dysfunctions contribute to motor neuron degeneration in ALS, the normal physiological functions of TDP-43 in astrocytes are largely unknown and whether the loss of astroglial TDP-43 contributes to ALS remains to be clarified. Here, we showed that TDP-43 deleted astrocytes showed cell-autonomously enhanced GFAP immunoreactivity without affecting astrocyte or microglia proliferation. At the transcriptomic level, TDP-43 deleted astrocytes resemble the A1-reactive astrocytes and induce microglia to increase C1q expression. These astrocytic changes do not cause the loss of motor neurons in spinal cords or denervation at the neuromuscular junctions. In contrast, there was a selective reduction of mature oligodendrocytes, but not oligodendrocyte precursor cells, suggesting a tri-glial dysfunction mediated by TDP-43-deleted astrocytes. Mice with astroglial TDP-43 deletion developed motor, but not sensory, deficits. Taken together, our results demonstrate that TDP-43 is required to maintain the protective functions of astrocytes relevant to the development of motor deficits in mice.

2020-11-01 | GSE156542 | GEO

Membralin deficiency dysregulates astrocytic glutamate homeostasis leading to ALS-like impairment

Project description:Mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are yet unclear. Specific deletion of the ER-component membralin in astrocytes manifested postnatal motor defects and lethality in mice, causing the accumulation of extracellular glutamate through reducing the glutamate transporter EAAT2. Restoring EAAT2 levels in membralin KO astrocytes limited astrocyte-dependent excitotoxicity in motor neurons. Transcriptomic profiles from mouse astrocytic membralin KO motor cortex indicateed significant perturbation in KEGG pathway components related to ALS, including downregulation of Eaat2 and upregulation of Tnfrsf1a. Changes in gene expression with membralin deletion also overlapped with mouse ALS models and reactive astrocytes. Our results shown that activation of TNF receptor (TNFR1)-NFkB pathway known to suppress Eaat2 transcription was upregulated with membralin deletion. Further, reduced membralin and EAAT2 levels correlated with disease progression in spinal cord from SOD1-mutant mouse models, and reductions in membralin/EAAT2 were observed in human ALS spinal cord. Importantly, overexpression of membralin in SOD1G93A astrocytes decreased TNFR1 levels and increased EAAT2 expression, and improved motor neuron survival. Importantly, upregulation of membralin in SOD1G93A mice significantly prolonged mouse survival. Together, our study provides a mechanism for ALS pathogenesis where membralin limits glutamatergic neurotoxicity, suggesting that modulating membralin has potential in ALS therapy

2019-05-07 | GSE130763 | GEO

Single-cell RNA-seq reveals neural progenitor subpopulations and divergent astrocyte lineages

Project description:Astrocytes are one of the most abundant cell types in the mammalian central nervous system. Their diversity was widely investigated in the adult brain recently. However, the heterogeneity of astrocyte progenitors in their early developmental stage is still not clear. In this study, we dissected the subpopulations of neural progenitor cells at the neurogenesis and the early gliogenesis stages by single-cell RNA sequencing analysis. Interestingly, we identified two astrocyte progenitor subgroups from the cerebral cortex. The astrocyte subgroups highly express Sparc or Sparcl1, which were reported have contrary functions in astrocytes to regulate synapse formation. Further analysis for subpopulations of neural progenitors from the ventral forebrain also identified two astrocyte progenitor subgroups, showing similar gene expression patterns as in the cortex. Surprisingly, clustering analysis between the subpopulations from the dorsal and the ventral forebrains showed that the astrocyte progenitors expressing Sparc or Sparcl1 were clustered together, irrespective of their derived regions. These results showed an early divergence of astrocyte progenitors and their cross-regional conservation at the start of gliogenesis during brain development.

2021-12-31 | GSE128948 | GEO

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