Neurodevelopmental abnormalities in neurosphere‐derived neural stem cells from SMN‐depleted mice

Shafey, Dina; MacKenzie, Alex; Kothary, Rashmi

doi:10.1002/jnr.21743

Cited by 35 publications

(24 citation statements)

References 29 publications

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“…SMA, a motoneuron developmental disorder, is caused by decrease in the amount of SMN protein [26, 27]. Intriguingly, we found the SMN reduced significantly along pMN differentiation, but expressed much higher in pMNs than GABA neurons.…”

Section: Discussionmentioning

confidence: 67%

Modeling the differential phenotypes of spinal muscular atrophy with high-yield generation of motor neurons from human induced pluripotent stem cells

Lin

Qian

et al. 2017

Oncotarget

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Spinal muscular atrophy (SMA) is a devastating motor neuron disease caused by mutations of the survival motor neuron 1 (SMN1) gene. SMN2, a paralogous gene to SMN1, can partially compensate for the loss of SMN1. On the basis of age at onset, highest motor function and SMN2 copy numbers, childhood-onset SMA can be divided into three types (SMA I-III). An inverse correlation was observed between SMN2 copies and the differential phenotypes of SMA. Interestingly, this correlation is not always absolute. Using SMA induced pluripotent stem cells (iPSCs), we found that the SMN was significantly decreased in both SMA III and SMA I iPSCs derived postmitotic motor neurons (pMNs) and γ-aminobutyric acid (GABA) neurons. Moreover, the significant differences of SMN expression level between SMA III (3 copies of SMN2) and SMA I (2 copies of SMN2) were observed only in pMNs culture, but not in GABA neurons or iPSCs. From these findings, we further discovered that the neurite outgrowth was suppressed in both SMA III and SMA I derived MNs. Meanwhile, the significant difference of neurite outgrowth between SMA III and SMA I group was also found in long-term cultures. However, significant hyperexcitability was showed only in SMA I derived mature MNs, but not in SMA III group. Above all, we propose that SMN protein is a major factor of phenotypic modifier. Our data may provide a new insight into recognition for differential phenotypes of SMA disease.

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Section: Discussionmentioning

confidence: 67%

Modeling the differential phenotypes of spinal muscular atrophy with high-yield generation of motor neurons from human induced pluripotent stem cells

Lin

Qian

et al. 2017

Oncotarget

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show abstract

“…Using cultured neurospheres from Smn-/-; SMN2 mice, Shafey and colleagues demonstrated that low Smn levels resulted in defects in neuronal differentiation and neuritogenesis [120]. Additional studies using in vitro models have shown that Smn accumulates in growth cones [121] and that reducing Smn levels leads to decreased axon outgrowth and growth cone size, attributable to defective beta-actin transport [122].…”

Section: The Contribution Of Developmental Pathways To Sma Pathogenesismentioning

confidence: 96%

Review: Neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophy

Murray

Talbot

Gillingwater

2010

Neuropathology and Applied Neurobiology

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2010) Neuropathology and Applied Neurobiology 36, 133-156 Neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophyAmid the great diversity of neurodegenerative conditions, there is a growing body of evidence that non-somatic (that is, synaptic and distal axonal) compartments of neurones are early and important subcellular sites of pathological change. In this review we discuss experimental data from human patients, animal models and in vitro systems showing that neuromuscular synapses are targeted in different forms of motor neurone disease (MND), including amyotrophic lateral sclerosis and spinal muscular atrophy. We highlight important developments revealing the heterogeneous nature of vulnerability in populations of lower motor units in MND and examine how progress in our understanding of the molecular pathways underlying MND may provide insights into the regulation of synaptic vulnerability and pathology. We conclude that future experiments developing therapeutic approaches specifically targeting neuromuscular synaptic vulnerability are likely to be required to prevent or delay disease onset and progression in human MND patients.

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“…Although SMA is often referred to as a motor neuron disease, recent evidence suggests that the splicing defects are present in multiple organs (Zhang et al 2008), and this can lead to diseaserelevant phenotypes in cells other than motor neurons (Hayhurst et al 2012). Surprisingly, neurospheres derived from the Smn À/À ;SMN2 mice, which represent a severe model of human SMA, did not differ in number when compared with wild type (Shafey et al 2008). Our data place PRMT5 upstream of SMN in the maturation cycle of Sm proteins in vivo.…”

Section: Role Of Prmt5 In Splicingmentioning

confidence: 99%

Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery

et al. 2013

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The tight control of gene expression at the level of both transcription and post-transcriptional RNA processing is essential for mammalian development. We here investigate the role of protein arginine methyltransferase 5 (PRMT5), a putative splicing regulator and transcriptional cofactor, in mammalian development. We demonstrate that selective deletion of PRMT5 in neural stem/progenitor cells (NPCs) leads to postnatal death in mice. At the molecular level, the absence of PRMT5 results in reduced methylation of Sm proteins, aberrant constitutive splicing, and the alternative splicing of specific mRNAs with weak 59 donor sites. Intriguingly, the products of these mRNAs are, among others, several proteins regulating cell cycle progression. We identify Mdm4 as one of these key mRNAs that senses the defects in the spliceosomal machinery and transduces the signal to activate the p53 response, providing a mechanistic explanation of the phenotype observed in vivo. Our data demonstrate that PRMT5 is a master regulator of splicing in mammals and uncover a new role for the Mdm4 pre-mRNA, which could be exploited for anti-cancer therapy.

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Neurodevelopmental abnormalities in neurosphere‐derived neural stem cells from SMN‐depleted mice

Cited by 35 publications

References 29 publications

Modeling the differential phenotypes of spinal muscular atrophy with high-yield generation of motor neurons from human induced pluripotent stem cells

Modeling the differential phenotypes of spinal muscular atrophy with high-yield generation of motor neurons from human induced pluripotent stem cells

Review: Neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophy

Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery

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