Hedgehog Signaling Regulates MyoD Expression and Activity

Voronova, Anastassia; Coyne, Erin; Madhoun, Ashraf Al; Fair, Joel; Bosiljcic, Neven; St-Louis, Catherine; Li, Grace; Thurig, Sherry; Wallace, Valerie A.; Wiper‐Bergeron, Nadine; Skerjanc, Ilona S.

doi:10.1074/jbc.m112.400184

Cited by 53 publications

(41 citation statements)

References 111 publications

(191 reference statements)

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“…This is similar to several studies in mice, in which Gli2 appears to be the primary transcriptional activator, while Gli1 is not required for embryonic development (Mo et al , 1997; Ding et al , 1998; Bai et al , 2002). Indeed, in P19 cells, Gli2 is upregulated rather than Gli1 after 5 days of cell differentiation (Voronova et al , 2013), which is similar to what is seen in our study. Moreover, reports have shown that Gli2 regulates Pax3 and MyoD expression during skeletal and cardiac myogenesis (Petropoulos et al , 2004; Voronova et al , 2013).…”

Section: Discussionsupporting

confidence: 90%

“…Studies have shown that Shh signaling is essential for myogenesis in zebrafish since without Shh signaling, adaxial cells are delayed in terminal differentiation (Coutelle et al , 2001). In mouse cells, hedgehog signaling regulates both cardiac and skeletal myogenesis, as the transcription factor of hedgehog signaling, Gli2, has been shown to regulate and activate Mef2c and MyoD expression, which are transcription factors needed for myogenic differentiation of progenitor cells (Voronova et al , 2012; Voronova et al , 2013). Shh signaling is also critical for neuronal development.…”

Section: Introductionmentioning

confidence: 99%

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Arsenic inhibits hedgehog signaling during P19 cell differentiation

Liu

Bain

2014

Toxicology and Applied Pharmacology

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Arsenic is a toxicant found in ground water around the world, and human exposure mainly comes from drinking water or from crops grown in areas containing arsenic in soils or water. Epidemiological studies have shown that arsenic exposure during development decreased intellectual function, reduced birth weight, and altered locomotor activity, while in vitro studies have shown that arsenite decreased muscle and neuronal cell differentiation. The sonic hedgehog (Shh) signaling pathway plays an important role during the differentiation of both neurons and skeletal muscle. The purpose of this study was to investigate whether arsenic can disrupt Shh signaling in P19 mouse embryonic stem cells, leading to changes muscle and neuronal cell differentiation. P19 embryonic stem cells were exposed to 0, 0.25, or 0.5 µM of sodium arsenite for up to 9 days during cell differentiation. We found that arsenite exposure significantly reduced transcript levels of genes in the Shh pathway in both a time and dose-dependent manner. This included the Shh ligand, which was decreased 2- to 3-fold, the Gli2 transcription factor, which was decreased 2- to 3-fold, and its downstream target gene Ascl1, which was decreased 5-fold. GLI2 protein levels and transcriptional activity were also reduced. However, arsenic did not alter GLI2 primary cilium accumulation or nuclear translocation. Moreover, additional extracellular SHH rescued the inhibitory effects of arsenic on cellular differentiation due to an increase in GLI binding activity. Taken together, we conclude that arsenic exposure affected Shh signaling, ultimately decreasing the expression of the Gli2 transcription factor. These results suggest a mechanism by which arsenic disrupts cell differentiation.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Arsenic inhibits hedgehog signaling during P19 cell differentiation

Liu

Bain

2014

Toxicology and Applied Pharmacology

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“…The expression of Gli1 was elevated on the 3rd and 9th days, but its expression declined on the 6th day. A similar expression profile of Gli1 and Gli2 was observed in dimethyl sulfoxide-induced P19 cells (Voronova et al, 2013).…”

Section: Discussionsupporting

confidence: 72%

“…Additionally, the repression of the Hh signaling pathway induced by cyclopamine or a small interfering RNA (siRNA) of its positive component inhibited chondrogenic differentiation (Wu et al, 2013). The Hh signaling pathway promotes myogenesis in zebrafish (Flynt et al, 2007;Lobbardi et al, 2011), Xenopus (Martin et al, 2007), mouse (Straface et al, 2009;Hu et al, 2012;Voronova et al, 2013), and chick (Elia et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Expression analysis of Gli1 and Gli2 in different tissues and muscle-derived cells of Qinchuan cattle

Liu¹,

Wang²,

Cheng³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The Hedgehog (Hh) signaling pathway regulates the differentiation of many kinds of cells and plays a critical role in many embryonic and postnatal developmental processes. Gli1 and Gli2 are two transcription factors of the Hh signaling pathway. In this study, we used quantitative real-time polymerase chain reaction to detect the relative expression of Gli1 and Gli2 in 13 tissues from three two-yearold purebred Qinchuan cattle, as well as in different cell populations derived from muscle and different stages of myogenic differentiation of myoblasts. The expression levels of Gli1 and Gli2 in muscle were the lowest of the 13 tissues (P < 0.05), and they declined predominantly from preplate (pp)1 to pp6 cells. However, the expression of Gli2 was elevated during myogenic differentiation until the 6th day. We speculated that Hh signaling was negatively activated in myocytes and quiescent myoblasts. The increased expression of Gli1 and Gli2 in the early days of myogenic differentiation suggested that Hh signaling would be activated when the quiescent bovine myoblast was stimulated to initiate myogenic differentiation.

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“…Among the Glis, Gli1 is the principal transcription factor in the Shh pathway, and many studies have shown that it is of great importance in skeletal muscle regeneration [20, 27, 28]. Furthermore, Gli2 activity has been confirmed to be sufficient and required for efficient MyoD treatment during skeletal myogenesis [29], which plays a major role in regulating muscle differentiation during embryogenesis and adult muscle regeneration [30]. Based on these data, we speculate that both Gli1 and Gli2 are crucial for the process by which Shh modulates skeletal muscle I/R injury.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Sonic Hedgehog Against Ischemia/Reperfusion Injury in Mouse Skeletal Muscle via AKT/mTOR/p70S6K Signaling

Zeng¹,

Fu²,

Wang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Skeletal muscle ischemia/reperfusion (I/R) injury is a common and severe disease. Sonic hedgehog (Shh) plays a critical role in post-natal skeletal muscle regeneration. In the present study, the role of Shh in skeletal muscle I/R injury and the mechanisms involved were investigated. Methods: The expression of Shh, AKT/mTOR/p70S6K and apoptosis pathway components were evaluated following tourniquet-induced skeletal muscle I/R injury. Then, mice were subjected to systemic administration of cyclopamine or one-shot treatment of a plasmid encoding the human Shh gene (phShh) to examine the effects of Shh on I/R injury. Moreover, mice were subjected to systemic administration of NVP-BEZ235 to investigate the role of the AKT/mTOR/p70S6K pathway in Shh-triggered skeletal muscle protection. Results: We found that the levels of Shh, AKT/mTOR/p70S6K pathway components and Cleaved Caspase 3 and the Bax/Bcl2 ratio initially increased and then decreased at different time points post-I/R injury. Moreover, Shh protected skeletal muscle against I/R injury by alleviating muscle destruction, reducing interstitial fibrosis and inhibiting apoptosis, and these protective effects were abrogated when the AKT/mTOR/p70S6K pathway was inhibited. Conclusion: Collectively, these data suggest that Shh signaling exerts a protective role through the AKT/mTOR/p70S6K signaling pathway during skeletal muscle I/R injury. Thus, Shh signaling may be a therapeutic target for protecting skeletal muscle from I/R injury.

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Hedgehog Signaling Regulates MyoD Expression and Activity

Cited by 53 publications

References 111 publications

Arsenic inhibits hedgehog signaling during P19 cell differentiation

Arsenic inhibits hedgehog signaling during P19 cell differentiation

Expression analysis of Gli1 and Gli2 in different tissues and muscle-derived cells of Qinchuan cattle

Protective Effects of Sonic Hedgehog Against Ischemia/Reperfusion Injury in Mouse Skeletal Muscle via AKT/mTOR/p70S6K Signaling

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