EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions

Wang, Yu Xin; Feige, Peter; Brun, Caroline E.; Hekmatnejad, Bahareh; Dumont, Nicolas A.; Renaud, Jean‐Marc; Faulkes, Sharlene; Guindon, Daniel E.; Rudnicki, Michael A.

doi:10.1016/j.stem.2019.01.002

Cited by 116 publications

(149 citation statements)

References 71 publications

(89 reference statements)

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“…1), which would obviate the need for cell isolation, expansion, and delivery. 41,42 This form of repair has been modeled in mice. 39 Gene therapy and gene editing are being tested for the purpose of replacing or restoring dystrophin in clinical trials (ClinicalTrials.gov numbers, NCT03368742, NCT03375164, and NCT03362502).…”

Section: Creates Reservoir Of Dystrophin-expressing Stem Cells and Mymentioning

confidence: 99%

Stem Cells in the Treatment of Disease

2019

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Section: Creates Reservoir Of Dystrophin-expressing Stem Cells and Mymentioning

confidence: 99%

Stem Cells in the Treatment of Disease

2019

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“…Immunostained images were optimized globally and assembled into figures with Photoshop. The minimum fiber Feret’s diameter ( Wang et al, 2019 ) was measured using ImageJ/Fiji software. Samples with significant staining artifacts were excluded from automated analyses.…”

Section: Methodsmentioning

confidence: 99%

Inducible Rpt3, a Proteasome Component, Knockout in Adult Skeletal Muscle Results in Muscle Atrophy

Kitajima

Suzuki

Yoshioka

et al. 2020

Front. Cell Dev. Biol.

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The ubiquitin–proteasome system has the capacity to degrade polyubiquitinated proteins and plays an important role in many cellular processes. However, the role of Rpt3 , a crucial proteasomal gene, has not been investigated in adult muscles in vivo . Herein, we generated skeletal-muscle-specific Rpt3 knockout mice, in which genetic inactivation of Rpt3 could be induced by doxycycline administration. The Rpt3 -knockout mice showed a significant reduction by more than 90% in the expression of Rpt3 in adult muscles. Using this model, we found that proteasome dysfunction in adult muscles resulted in muscle wasting and a decrease in the myofiber size. Immunoblotting analysis showed that the amounts of ubiquitinated proteins were markedly higher in muscles of Rpt3 -deficient mice than in those of the control mice. Analysis of the autophagy pathway in the Rpt3 -deficient mice showed that the upregulation of LC3II, p62, Atg5, Atg7, and Beclin-1 in protein levels, which supposed to be compensatory proteolysis activation. Our results suggest that the proteasome inhibition in adult muscle severely deteriorates myofiber integrity and results in muscle atrophy.

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“…Whether PAX7-expression is directly or indirectly affected by TACC3 remains unclear, but we note that TACC3 regulates subcellular localization and physical association of transcription factors to control hematopoeiesis (27) Satellite Cell Expansion and Self-Renewal Ex Vivo and In Vivo Requires TACC3 TACC3 is amongst several substrates of AuroraA kinase that influence mitotic spindle assembly (17). An EGFR-AuroraA kinase signaling pathway orients the mitotic spindle apicobasally to facilitate asymmetric cell divisions to maintain the satellite cell pool (3). It is unknown whether TACC3 regulates the orientation of the mitotic spindle, but we show that TACC3 depletion preferentially reduces the 'reserve cell' population of satellite cells undergoing self-renewal ex vivo.…”

Section: P-eif2a Dependent Tacc3 Translation Permits Satellite Cell Ementioning

confidence: 97%

“…Activated satellite cells exhibit remarkable proliferative capacity to rapidly expand the population of myogenic progenitors required to efficiently regenerate muscle. Moreover, this proliferative phase is marked by symmetric cell divisions which drive expansion of the satellite cell pool and asymmetric cell divisions, mediated in part through an EGFR-AuroraA kinase signaling pathway, which ensure satellite cell self-renewal (3). How satellite cells achieve this proliferative capacity, while maintaining the fidelity of cell division, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Satellite cell expansion is mediated by P-eIF2α dependentTacc3translation

Fujita

Lean

Jamet³

et al. 2020

Preprint

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Translational control of gene expression is an important regulator of adult stem cell quiescence, activation and self-renewal. In skeletal muscle, quiescent satellite cells maintain low levels of protein synthesis, mediated in part through the phosphorylation of eIF2a (P-eIF2a).Pharmacological inhibition of the eIF2a phosphatase with the small molecule sal003 maintains P-eIF2a and permits the expansion of satellite cells ex vivo. Paradoxically, P-eIF2a also increases the translation of specific mRNAs, which is mediated by P-eIF2a dependent readthrough of inhibitory upstream open reading frames (uORFs). Here, we ask whether P-eIF2a dependent mRNA translation enables expansion of satellite cells. Using transcriptomic and proteomic analyses, we show a number of genes associated with the assembly of the spindle pole to be upregulated at the level of protein, without corresponding change in mRNA levels, in satellite cells expanded in the presence of sal003. We show that uORFs in the 5'UTR of mRNA for the mitotic spindle stability gene Tacc3 direct P-eIF2a dependent translation. Satellite cells deficient for TACC3 exhibit defects in expansion, self-renewal and regeneration of skeletal muscle. SignificanceTranslational control of gene expression has emerged as an important regulator of adult stem cell populations, which maintain low levels of protein synthesis. In adult muscle stem cells, or satellite cells, a portrait of translational control has emerged whereby multiple repression mechanisms prevent the translation of specific mRNAs. It remains unclear how other mRNAs escape repression and are efficiently translated. We show that within the context of low global rates of protein synthesis, satellite cell expansion occurs through the selective translation of Tacc3 mRNA. Tacc3 deficient satellite cells expand poorly, leading to defects in skeletal muscle regeneration. Our study provides a more complete picture of translational control of gene expression in adult stem cell populations.

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EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions

Abstract: Highlights d EGFR expression and activation are polarized in satellite cells d EGF stimulates asymmetric satellite stem cell division d Polarized EGFR activation orients mitotic centrosomes through Aurka d EGF stimulation rescues mdx satellite cell function in vitro and in vivo

Cited by 116 publications

References 71 publications

Stem Cells in the Treatment of Disease

Stem Cells in the Treatment of Disease

Inducible Rpt3, a Proteasome Component, Knockout in Adult Skeletal Muscle Results in Muscle Atrophy

Satellite cell expansion is mediated by P-eIF2α dependentTacc3translation

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