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Transcriptome profiling of severe spinal muscular atrophy mouse embryonic stem cell-derived motor neurons

ABSTRACT: Proximal spinal muscular atrophy (SMA) is an early onset, autosomal recessive motor neuron disease caused by loss of or mutation in SMN1 (survival motor neuron 1). Despite understanding the genetic basis underlying this disease, it is still not known why motor neurons (MNs) are selectively affected by the loss of the ubiquitously expressed SMN protein. Using a mouse embryonic stem cell (mESC) model for severe SMA, the RNA transcript profiles (transcriptomes) between control and severe SMA (SMN2+/+;mSmn-/-) mESC-derived MNs were compared in this study using massively parallel RNA sequencing (RNA-Seq). The MN differentiation efficiencies between control and severe SMA mESCs were similar. RNA-Seq analysis identified 3094 upregulated and 6964 downregulated transcripts in SMA mESC-derived MNs when compared against control cells. Pathway and network analysis of the differentially expressed RNA transcripts showed that pluripotency and cell proliferation transcripts were significantly increased in SMA MNs while transcripts related to neuronal development and activity were reduced. The differential expression of selected transcripts such as Crabp1, Crabp2 and Nkx2.2 was validated in a second mESC model for SMA as well as in the spinal cords of low copy SMN2 severe SMA mice. Furthermore, the levels of these selected transcripts were restored in high copy SMN2 rescue mouse spinal cords when compared against low copy SMN2 severe SMA mice. These findings suggest that SMN deficiency affects processes critical for normal development and maintenance of MNs.

ORGANISM(S): Mus musculus

PROVIDER: GSE56284 | GEO | 2014/09/08

SECONDARY ACCESSION(S): PRJNA242839

REPOSITORIES: GEO

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Transcriptome profiling of severe spinal muscular atrophy mouse embryonic stem cell-derived motor neurons

Project description:Proximal spinal muscular atrophy (SMA) is an early onset, autosomal recessive motor neuron disease caused by loss of or mutation in SMN1 (survival motor neuron 1). Despite understanding the genetic basis underlying this disease, it is still not known why motor neurons (MNs) are selectively affected by the loss of the ubiquitously expressed SMN protein. Using a mouse embryonic stem cell (mESC) model for severe SMA, the RNA transcript profiles (transcriptomes) between control and severe SMA (SMN2+/+;mSmn-/-) mESC-derived MNs were compared in this study using massively parallel RNA sequencing (RNA-Seq). The MN differentiation efficiencies between control and severe SMA mESCs were similar. RNA-Seq analysis identified 3094 upregulated and 6964 downregulated transcripts in SMA mESC-derived MNs when compared against control cells. Pathway and network analysis of the differentially expressed RNA transcripts showed that pluripotency and cell proliferation transcripts were significantly increased in SMA MNs while transcripts related to neuronal development and activity were reduced. The differential expression of selected transcripts such as Crabp1, Crabp2 and Nkx2.2 was validated in a second mESC model for SMA as well as in the spinal cords of low copy SMN2 severe SMA mice. Furthermore, the levels of these selected transcripts were restored in high copy SMN2 rescue mouse spinal cords when compared against low copy SMN2 severe SMA mice. These findings suggest that SMN deficiency affects processes critical for normal development and maintenance of MNs. RNA profiles were generated from FACS-purified control and SMA mESC-derived motor neurons (n=3/genotype) by deep sequencing using Illumina HighSeq 2500

2014-09-08 | E-GEOD-56284 | biostudies-arrayexpress

Gene expression profiling of LMC and MMC motor neurons in SMA mice

Project description:Spinal muscular atrophy (SMA) is a neurodegenerative disease which exhibits selective motor neuron death caused by a ubiquitous deficiency of the survival motor neuron (SMN) protein. It remains unclear how the ubiquitous reduction of SMN lead to death in selective motor neuron pools. Medial motor neuron columns (MMC) are vulnerable, whereas lateral motor columns (LMC) are resistant to motor neuron death in SMA. Here we performed microarray and pathway analysis comparing cholera toxin subunit B (CTb) labeled vulnerable MMC and resistant LMC of pre-symptomatic SMA with corresponding motor neuron columns of control mice to identify pathways involved in selective motor neuron death in SMA. WT is FVB. SMN is Delta7 (SMNΔ7;SMN2;Smn-) on a FVB background.

2017-12-12 | GSE81245 | GEO

Modeling the early phenotype at the neuromuscular junction of spinal muscular atrophy using patient-derived iPSCs (RNA-Seq)

Project description:Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the survival of motor neuron 1 (SMN1) gene. In the pathogenesis of SMA, pathological changes of the neuromuscular junction (NMJ) precede the motor neuronal loss. Therefore, it is critical to evaluate the NMJ formed by SMA patientsM-bM-^@M-^Y motor neurons (MNs), and to identify drugs that can restore the normal condition. We generated NMJ-like structures using motor neurons (MNs) derived from SMA patient-specific induced pluripotent stem cells (iPSCs), and found that the clustering of the acetylcholine receptor (AChR) is significantly impaired. Valproic acid and antisense oligonucleotide treatment ameliorated the AChR clustering defects, leading to an increase in the level of full-length SMN transcripts. Thus, the current in vitro model of AChR clustering using SMA patient-derived iPSCs is useful to dissect the pathophysiological mechanisms underlying the development of SMA, and to evaluate the efficacy of new therapeutic approaches.M-bM-^@M-^C to evaluate the effects of VPA on the expression profiles of the MNs

2015-02-03 | E-GEOD-65508 | biostudies-arrayexpress

Selective Death in Spinal Muscular Atrophy: Genome-Wide RNA-Seq Using Purified Patient-Derived Motor Neurons

Project description:Spinal Muscular Atrophy (SMA) is well-known to be caused by mutations in the gene Survival of Motor Neuron 1 (SMN1). Because this gene is ubiquitously expressed, it remains poorly understood why motor neurons (MNs) are one of the most affected cell types. To begin to address this question, we carried out RNA-sequencing studies using fixed, antibody-labeled and purified MNs produced from control and SMA patient-derived induced pluripotent stem cells (iPSCs). We found SMA-specific changes in MNs, including hyper-activation of the endoplasmic reticulum (ER) stress pathway and enhanced apoptosis. Functional studies demonstrated that inhibition of ER stress improves overall MN health and survival in vitro even in MNs with low SMN levels. In SMA mice, we show that systemic delivery of an ER stress inhibitor that crosses the blood-brain-barrier led to preservation of MNs in the spinal cord and prolonged survival of these mice. Therefore, our study implies that selective activation of ER stress underlies MN death in SMA. Moreover, the approach we have taken would be broadly applicable to studying disease-prone human cells in heterogeneous cultures. total RNA collected from ES cell and patient ES cell derived spinal motor neurons

2015-09-01 | E-GEOD-69175 | biostudies-arrayexpress

Modeling the early phenotype at the neuromuscular junction of spinal muscular atrophy using patient-derived iPSCs

Project description:Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the survival of motor neuron 1 (SMN1) gene. In the pathogenesis of SMA, pathological changes of the neuromuscular junction (NMJ) precede the motor neuronal loss. Therefore, it is critical to evaluate the NMJ formed by SMA patientsM-bM-^@M-^Y motor neurons (MNs), and to identify drugs that can restore the normal condition. We generated NMJ-like structures using motor neurons (MNs) derived from SMA patient-specific induced pluripotent stem cells (iPSCs), and found that the clustering of the acetylcholine receptor (AChR) is significantly impaired. Valproic acid and antisense oligonucleotide treatment ameliorated the AChR clustering defects, leading to an increase in the level of full-length SMN transcripts. Thus, the current in vitro model of AChR clustering using SMA patient-derived iPSCs is useful to dissect the pathophysiological mechanisms underlying the development of SMA, and to evaluate the efficacy of new therapeutic approaches.M-bM-^@M-^C To compare the gene expression pattern between control and patient derived iPSCs

2015-01-31 | E-GEOD-65470 | biostudies-arrayexpress

Next Generation Sequencing of human SMA and healthy control Motor Neurons

Project description:Spinal muscular atrophy (SMA) is a motor neuron (MN) disorder caused by mutations in SMN1. The reasons of MNs selective vulnerability linked to SMN reduction remain unclear. To address this question, we performed deep RNA sequencing on SMA human MNs to detect specific altered splicing/expressed genes and to identify the presence of a common sequence motif in these genes. Many deregulated genes, such as Neurexin and Synaptotagmin families, are implicated in critical MN-function like axonogenesis and synapses. Motif-enrichment analyses of differentially expressed/spliced genes, including Neurexin2 (NRXN2), revealed a common Motif, Motif-7, which is target of SYNCRIP protein. Interestingly, SYNCRIP interacts only with full-length SMN, binding and modulating several MN transcripts, including SMN itself. SYNCRIP overexpression rescued SMA-MNs, due to the consequent increase of SMN and their down-stream target NRXN2, through a positive loop mechanism. SMN/SYNCRIP complex through motif-7 might account for selective MN degeneration and represent a potential therapeutic target.

2018-10-12 | GSE108094 | GEO

Expression data from SMA fibroblasts treated with amiloride or EIPA

Project description:Spinal muscular atrophy (SMA) is an autosomal recessive, pediatric-onset disorder caused by the loss of spinal motor neurons thereby leading to generalized muscle atrophy. SMA is caused by the loss of or mutations in the survival motor neuron 1 (SMN1) gene. SMN1 is duplicated only in human to give rise to the paralogous SMN2 gene. These paralogs are nearly identical except for a cytosine to thymine (C-to-T) transition within an exonic splicing enhancer (ESE) element within exon 7. As a result, the majority of SMN2 transcripts lack exon 7 (SMNΔ7) which produces a truncated and unstable SMN protein. Since SMN2 copy number is inversely related to disease severity, it is a well-established target for SMA therapeutics development. 5-(N-ethyl-N-isopropyl)amiloride (EIPA), an inhibitor of sodium/proton exchangers (NHEs), has previously been shown to increase exon 7 inclusion and SMN protein levels in SMA cells. In this study several different types of NHE inhibitors were evaluated for their ability to modulate SMN2 expression. EIPA as well as 5-(N,N-hexamethylene)amiloride (HMA) increase exon 7 inclusion in SMN2 splicing reporter lines as well as in SMA fibroblasts. The EIPA-induced exon 7 inclusion occurs via a mechanism unique from that used by RG7800, another SMN2 splicing modulator, and does not involve previously identified splicing factors. Transcriptome analysis identified novel targets, including TIA1 and FABP3, for further characterization. EIPA and HMA are more selective at inhibiting the NHE5 isoform, which is expressed in fibroblasts as well as in neuronal cells. These results show that NHE5 inhibition increases SMN2 expression and may be a novel target for therapeutics development.

2022-06-16 | GSE179861 | GEO

Multi-omic analysis identifies APC/C-mediated degradation of SMN in neurons

Project description:Spinal muscular atrophy (SMA) due to loss-of-function of SMN protein is associated with severe loss of voluntary muscle control and is a leading inherited cause of infant mortality. SMA treatments will benefit from in-depth knowledge of functional pathways disrupted in disease and identification of SMN modulators. Here, we present a comprehensive temporal profile of proteogenomic expression patterns in developing mouse spinal cords (Δ7 model), alongside endpoint analyses of human spinal and ventral root tissues in SMA disease, identifying targets for assessing disease progression and treatment response. SMA disease results in development-associated deficiencies in transcription, translation initiation, intracellular transport, and protein folding, and diminished RNA translation efficiency for proteins important in axon development/myelination. The broad impact of SMN deficiency prompted the search for co-regulated proteins that modulate SMN protein levels, resulting in identification of the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin ligase as a potential modulator of SMN protein stability. Functional studies of APC/C showed that both SMN and HuD are specific interactors of the APC/C in neurons and that selective APC/C inhibition significantly limited SMN and HuD degradation. Finally, we demonstrate that APC/C inhibition rescues motor axon defects characteristic of SMA in a zebrafish model of SMA disease.

2022-01-18 | GSE128129 | GEO

Type I PRMT inhibitor MS023 promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue the phenotype of SMA mice

Project description:In our study we have identified MS023, an inhibitor of PRMTs, to increase SMN protein and FL SMN2 transcript levels, and to improve survival and weights of treated SMA mice, alone and in combination with currently approved antisense oligonucleotide. In order to understand the molecular underpinnings of the added benefit provided by the combinatorial treatment, we performed bulk transcriptomic analysis in spinal cords of SMA mice treated with MS023 only, nusinersen only, and MS023 in combination with nusinersen, compared to wild type and SMA littermates.

2023-03-01 | GSE206400 | GEO

Modeling the early phenotype at the neuromuscular junction of spinal muscular atrophy using patient-derived iPSCs

Project description:Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the survival of motor neuron 1 (SMN1) gene. In the pathogenesis of SMA, pathological changes of the neuromuscular junction (NMJ) precede the motor neuronal loss. Therefore, it is critical to evaluate the NMJ formed by SMA patients’ motor neurons (MNs), and to identify drugs that can restore the normal condition. We generated NMJ-like structures using motor neurons (MNs) derived from SMA patient-specific induced pluripotent stem cells (iPSCs), and found that the clustering of the acetylcholine receptor (AChR) is significantly impaired. Valproic acid and antisense oligonucleotide treatment ameliorated the AChR clustering defects, leading to an increase in the level of full-length SMN transcripts. Thus, the current in vitro model of AChR clustering using SMA patient-derived iPSCs is useful to dissect the pathophysiological mechanisms underlying the development of SMA, and to evaluate the efficacy of new therapeutic approaches.

2015-01-31 | GSE65470 | GEO

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