EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions
Copyright © 2019 Elsevier Inc. All rights reserved..
Loss of dystrophin expression in Duchenne muscular dystrophy (DMD) causes progressive degeneration of skeletal muscle, which is exacerbated by reduced self-renewing asymmetric divisions of muscle satellite cells. This, in turn, affects the production of myogenic precursors and impairs regeneration and suggests that increasing such divisions may be beneficial. Here, through a small-molecule screen, we identified epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurka) as regulators of asymmetric satellite cell divisions. Inhibiting EGFR causes a substantial shift from asymmetric to symmetric division modes, whereas EGF treatment increases asymmetric divisions. EGFR activation acts through Aurka to orient mitotic centrosomes, and inhibiting Aurka blocks EGF stimulation-induced asymmetric division. In vivo EGF treatment markedly activates asymmetric divisions of dystrophin-deficient satellite cells in mdx mice, increasing progenitor numbers, enhancing regeneration, and restoring muscle strength. Therefore, activating an EGFR-dependent polarity pathway promotes functional rescue of dystrophin-deficient satellite cells and enhances muscle force generation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Cell stem cell - 24(2019), 3 vom: 07. März, Seite 419-432.e6 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Yu Xin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.04.2020 Date Revised 23.04.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.stem.2019.01.002 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM293398909 |
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| 100 | 1 | |a Wang, Yu Xin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions |
| 264 | 1 | |c 2019 | |
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| 500 | |a Date Completed 23.04.2020 | ||
| 500 | |a Date Revised 23.04.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 Elsevier Inc. All rights reserved. | ||
| 520 | |a Loss of dystrophin expression in Duchenne muscular dystrophy (DMD) causes progressive degeneration of skeletal muscle, which is exacerbated by reduced self-renewing asymmetric divisions of muscle satellite cells. This, in turn, affects the production of myogenic precursors and impairs regeneration and suggests that increasing such divisions may be beneficial. Here, through a small-molecule screen, we identified epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurka) as regulators of asymmetric satellite cell divisions. Inhibiting EGFR causes a substantial shift from asymmetric to symmetric division modes, whereas EGF treatment increases asymmetric divisions. EGFR activation acts through Aurka to orient mitotic centrosomes, and inhibiting Aurka blocks EGF stimulation-induced asymmetric division. In vivo EGF treatment markedly activates asymmetric divisions of dystrophin-deficient satellite cells in mdx mice, increasing progenitor numbers, enhancing regeneration, and restoring muscle strength. Therefore, activating an EGFR-dependent polarity pathway promotes functional rescue of dystrophin-deficient satellite cells and enhances muscle force generation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Aurka | |
| 650 | 4 | |a Duchenne muscular dystrophy | |
| 650 | 4 | |a EGF | |
| 650 | 4 | |a EGFR | |
| 650 | 4 | |a apicobasal polarity | |
| 650 | 4 | |a asymmetric cell division | |
| 650 | 4 | |a muscle stem cell | |
| 650 | 4 | |a satellite cell | |
| 650 | 4 | |a skeletal muscle | |
| 650 | 7 | |a Dystrophin |2 NLM | |
| 650 | 7 | |a EGFR protein, human |2 NLM | |
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| 650 | 7 | |a EGFR protein, mouse |2 NLM | |
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| 650 | 7 | |a ErbB Receptors |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a AURKA protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Aurka protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Aurora Kinase A |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 700 | 1 | |a Feige, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Brun, Caroline E |e verfasserin |4 aut | |
| 700 | 1 | |a Hekmatnejad, Bahareh |e verfasserin |4 aut | |
| 700 | 1 | |a Dumont, Nicolas A |e verfasserin |4 aut | |
| 700 | 1 | |a Renaud, Jean-Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Faulkes, Sharlene |e verfasserin |4 aut | |
| 700 | 1 | |a Guindon, Daniel E |e verfasserin |4 aut | |
| 700 | 1 | |a Rudnicki, Michael A |e verfasserin |4 aut | |
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