Transcriptome Profiling of Spinal Muscular Atrophy Motor Neurons Derived from Mouse Embryonic Stem Cells

Matsushima, Miho; Harris, Ashlee W.; Kingham, Brewster F.; Lumpkin, Casey J.; Opdenaker, Lynn M.; McCahan, Suzanne M.; Wang, Wenlan; Butchbach, Matthew E.R.

doi:10.1371/journal.pone.0106818

Cited by 39 publications

(43 citation statements)

References 102 publications

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“…Of this group, only Igfbp2 was significantly changed (~1.7-fold increase in skip versus therapeutic ASO-treated mice). This discordance between gene expression and protein changes has been observed in other models of SMN [21]. Notably, although gemin 2 and gemin 8 were not altered at the level of gene expression, the protein levels of both significantly increased with therapeutic ASO treatment, consistent with the observation that SMN stabilizes gemin proteins [3].…”

Section: Induced Transcriptional Changes Can Be Prevented or Reversedsupporting

confidence: 82%

“…Whether gems or the closely associated Cajal bodies couple their roles in splicing and transcription with the DNA damage response is unknown. Although we cannot rule out the contribution of reactive glial proliferation to cell cycle expression changes in the SMA model, a recent study showed that purified motor neuron precursors derived from mouse SMA embryonic stem cells (ESCs) also show marked up-regulation of cell proliferation genes or proteins, including p21, encoded by Cdkn1a [21]. Curiously, p21 levels are up-regulated over 40-fold in SMA mESCs compared to control mESCs, whereas Cdkn1a mRNA levels are down-regulated 0.76-fold [21].…”

Section: Discussionmentioning

confidence: 99%

“…Although we cannot rule out the contribution of reactive glial proliferation to cell cycle expression changes in the SMA model, a recent study showed that purified motor neuron precursors derived from mouse SMA embryonic stem cells (ESCs) also show marked up-regulation of cell proliferation genes or proteins, including p21, encoded by Cdkn1a [21]. Curiously, p21 levels are up-regulated over 40-fold in SMA mESCs compared to control mESCs, whereas Cdkn1a mRNA levels are down-regulated 0.76-fold [21]. Together, these data suggest that post-transcriptional and post-translational regulation of certain mRNAs and proteins disrupted in SMA may depend on the cell cycle status of the cells studied (e.g.…”

Section: Discussionmentioning

confidence: 99%

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Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7

et al. 2015

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Spinal muscular atrophy (SMA) is a neuromuscular disease caused by disruption of the survival motor neuron 1 (SMN1) gene, partly compensated for by the paralogous gene SMN2. Exon 7 inclusion is critical for full-length SMN protein production and occurs at a much lower frequency for SMN2 than for SMN1. Antisense oligonucleotide (ASO)-mediated blockade of an intron 7 splicing silencer was previously shown to promote inclusion of SMN2 exon 7 in SMA mouse models and mediate phenotypic rescue. However, downstream molecular consequences of this ASO therapy have not been defined. Here we characterize the gene-expression changes that occur in an induced model of SMA and show substantial rescue of those changes in central nervous system tissue upon intracerebroventricular administration of an ASO that promotes inclusion of exon 7, with earlier administration promoting greater rescue. This study offers a robust reference set of preclinical pharmacodynamic gene expression effects for comparison of other investigational therapies for SMA.

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Section: Induced Transcriptional Changes Can Be Prevented or Reversedsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7

et al. 2015

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“…Previously, low levels of SMN have been linked to widespread changes in expression patterns, [121][122][123][124][125][126][127][128] but it is currently an open question as to how these changes might be linked to Cajal bodies. In addition, the mechanism by which these conformational changes in the nucleus affect the rest of the cell and which cellular components and processes are most severely affected has yet to be studied.…”

Section: Smn and Cajal Body Structurementioning

confidence: 99%

SMN - A chaperone for nuclear RNP social occasions?

2016

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Survival Motor Neuron (SMN) protein localizes to both the nucleus and the cytoplasm. Cytoplasmic SMN is diffusely localized in large oligomeric complexes with core member proteins, called Gemins. Biochemical and cell biological studies have demonstrated that the SMN complex is required for the cytoplasmic assembly and nuclear transport of Sm-class ribonucleoproteins (RNPs). Nuclear SMN accumulates with spliceosomal small nuclear (sn)RNPs in Cajal bodies, sub-domains involved in multiple facets of snRNP maturation. Thus, the SMN complex forms stable associations with both nuclear and cytoplasmic snRNPs, and plays a critical role in their biogenesis. In this review, we focus on potential functions of the nuclear SMN complex, with particular emphasis on its role within the Cajal body.

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“…However, homologs of NALCN are expressed in the neuromuscular junction in D. melanogaster 18 as well as in motor neurons in C. elegans 19 and mice. 20,21 Accordingly, mutations in NALCN might cause congenital contractures by disturbing motor control of myofiber function during development, similar to the hypothesized effects of mutations in ECEL1, PIEZO2, and CHRNG (MIM 100730).…”

mentioning

confidence: 91%

De Novo Mutations in NALCN Cause a Syndrome Characterized by Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay

Beck

Armenteros

Nkinsi

et al. 2015

The American Journal of Human Genetics

137

152

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Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).

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Transcriptome Profiling of Spinal Muscular Atrophy Motor Neurons Derived from Mouse Embryonic Stem Cells

Cited by 39 publications

References 102 publications

Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7

Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7

SMN - A chaperone for nuclear RNP social occasions?

De Novo Mutations in NALCN Cause a Syndrome Characterized by Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay

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