Oligodendrocyte development and CNS myelination are unaffected in a mouse model of severe spinal muscular atrophy

O’Meara, Ryan W.; Cummings, Sarah E.; Repentigny, Yves De; McFall, Emily; Michalski, John-Paul; Deguise, Marc-Olivier; Gibeault, Sabrina; Kothary, Rashmi

doi:10.1093/hmg/ddw385

Cited by 8 publications

(6 citation statements)

References 36 publications

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“…Ddx20 -null mice and Smn1- null mice die at different stages, with Ddx20 -null embryos demonstrating lethality as early as the four-cell stage [ 14 ], whereas Smn1 -null embryos show lethality after the morula stage [ 34 ]. Furthermore, SMA model mice ( Smn1 −/− ; SMN2 mice) do not demonstrate changes in OPC proliferation and/or oligodendrocyte differentiation [ 35 ]. These differences suggest that Ddx20 plays other roles, in addition to acting as a component of the SMN complex.…”

Section: Discussionmentioning

confidence: 99%

Ddx20, an Olig2 binding factor, governs the survival of neural and oligodendrocyte progenitor cells via proper Mdm2 splicing and p53 suppression

et al. 2022

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Olig2 is indispensable for motoneuron and oligodendrocyte fate-specification in the pMN domain of embryonic spinal cords, and also involved in the proliferation and differentiation of several cell types in the nervous system, including neural progenitor cells (NPCs) and oligodendrocytes. However, how Olig2 controls these diverse biological processes remains unclear. Here, we demonstrated that a novel Olig2-binding protein, DEAD-box helicase 20 (Ddx20), is indispensable for the survival of NPCs and oligodendrocyte progenitor cells (OPCs). A central nervous system (CNS)-specific Ddx20 conditional knockout (cKO) demonstrated apoptosis and cell cycle arrest in NPCs and OPCs, through the potentiation of the p53 pathway in DNA damage-dependent and independent manners, including SMN complex disruption and the abnormal splicing of Mdm2 mRNA. Analyzes of Olig2 null NPCs showed that Olig2 contributed to NPC proliferation through Ddx20 protein stabilization. Our findings provide novel mechanisms underlying the Olig2-mediated proliferation of NPCs, via the Ddx20-p53 axis, in the embryonic CNS.

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Section: Discussionmentioning

confidence: 99%

Ddx20, an Olig2 binding factor, governs the survival of neural and oligodendrocyte progenitor cells via proper Mdm2 splicing and p53 suppression

et al. 2022

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“…Whether OL lineages are involved in SMA pathogenesis is controversial. O'Meara et al found that OL growth, migration, differentiation, and myelination were not affected in severe SMA mice (Smn −/− , SMN2 +/+ ) [82]. However, Kazuki Ohuchi et al found that the OL lineage was impaired in Δ7 SMA mice [83].…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

Sun

Qiu

Yang

et al. 2022

Preprint

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Although spinal muscular atrophy (SMA) is a motor neuron disease caused by the loss of survival of motor neuron proteins, there is growing evidence that lesions in nonmotor neuron cells are involved in SMA pathogenesis. Transcriptome alterations occurring at the single-cell level in SMA spinal cord are unknown. Here, we performed single-cell RNA sequencing of the spinal cord of a severe SMA mouse model, and characterized ten cell types as well as their differentially expressed genes. Using CellChat, we found that cellular communication between different cell types in the spinal cord of SMA mice is substantially reduced. A dimensionality reduction analysis revealed 29 cell subtypes and differentially expressed genes for each subtype. Among them, the most significant change in the SMA spinal cord at the single-cell level was observed in a subpopulation of vascular fibroblasts. This subpopulation was greatly reduced, which may be responsible for vascular defects in SMA mice and may lead to widespread reductions in protein synthesis and energy metabolism. This study is the first to report a single-cell atlas of the spinal cord of mice with severe SMA, providing new insights into SMA pathogenesis.

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“…We detected dysregulation of myelin gene splicing, which was similar to that in quaking viable ( qk v ) mice, classical demyelination mutants (Wu et al, 2002). Although oligodendrocyte development and CNS myelination were unaffected in SMA model mice ( Smn1 −/− ; SMN2 mice) (O'Meara et al, 2017), SMN2 may be able to compensate for the loss of Smn1 function. In mouse genome, only one Smn gene, Smn1 , is encoded, and Smn1 KO mice show early lethality at the peri‐implantation stage (Schrank et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Ddx20, DEAD box helicase 20, is essential for the differentiation of oligodendrocyte and maintenance of myelin gene expression

Simankova

Bizen

Saitoh

et al. 2021

Glia

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Oligodendrocytes form myelin sheaths that surround axons, contributing to saltatory conduction and proper central nervous system (CNS) function. Oligodendrocyte progenitor cells (OPCs) are generated during the embryonic stage and differentiate into myelinating oligodendrocytes postnatally. Ddx20 is a multifunctional, DEAD-box helicase involved in multiple cellular processes, including transcription, splicing, micro-RNA biogenesis, and translation. Although defects in each of these processes result in abnormal oligodendrocyte differentiation and myelination, the involvement of Ddx20 in oligodendrocyte terminal differentiation remains unknown. To address this question, we used Mbp-Cre mice to generate Ddx20 conditional knockout (cKO) mice to allow for the deletion of Ddx20 from mature oligodendrocytes. Mbp-Cre;Ddx20 cKO mice demonstrated small body sizes, behavioral abnormalities, muscle weakness, and short lifespans, with mortality by the age of 2 months old. Histological analyses demonstrated significant reductions in the number of mature oligodendrocytes and drastic reductions in the expression levels of myelin-associated mRNAs, such as Mbp and Plp at postnatal day 42. The number of OPCs did not change. A thin myelin layer was observed for large-diameter axons in Ddx20 cKO mice, based on electron microscopic analysis. A bromodeoxyuridine (BrdU) labeling experiment demonstrated that terminal differentiation was perturbed from ages 2 weeks to 7 weeks in the CNS of Mbp-Cre;Ddx20 cKO mice. The activation of mitogen-activated protein (MAP) kinase, which promotes myelination, was downregulated in the Ddx20 cKO mice based on immunohistochemical detection. These results indicate that Ddx20 is an essential factor for terminal differentiation of oligodendrocytes and maintenance of myelin gene expression.

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Oligodendrocyte development and CNS myelination are unaffected in a mouse model of severe spinal muscular atrophy

Cited by 8 publications

References 36 publications

Ddx20, an Olig2 binding factor, governs the survival of neural and oligodendrocyte progenitor cells via proper Mdm2 splicing and p53 suppression

Ddx20, an Olig2 binding factor, governs the survival of neural and oligodendrocyte progenitor cells via proper Mdm2 splicing and p53 suppression

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

Ddx20, DEAD box helicase 20, is essential for the differentiation of oligodendrocyte and maintenance of myelin gene expression

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