MyoD regulates apoptosis of myoblasts through microRNA-mediated down-regulation of Pax3

Hirai, Hiroyuki; Verma, Mayank; Watanabe, Shuichi; Tastad, Christopher; Asakura, Yoko; Asakura, Atsushi

doi:10.1083/jcb.201006025

Cited by 172 publications

(186 citation statements)

References 68 publications

Supporting

Mentioning

178

Contrasting

Order By: Relevance

“…The behavior of adult muscle stem cells-particularly their proliferation, differentiation, and apoptosis-is regulated by Pax3 and the closely related Pax7. The protein levels of Pax3/7 were recently demonstrated to be tightly regulated by miRNAs, including miR-27b and miR-206 (12,40,41). Thus, embryonic myoblasts and adult muscle stem cells require mechanisms to tightly regulate Pax3/ Pax7 activity.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA regulation of the paired-box transcription factor Pax3 confers robustness to developmental timing of myogenesis

Goljanek‐Whysall¹,

Sweetman²,

Abu‐Elmagd³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

120

121

View full text Add to dashboard Cite

Commitment of progenitors in the dermomyotome to myoblast fate is the first step in establishing the body musculature. Pax3 is a crucial transcription factor, important for skeletal muscle development and expressed in myogenic progenitors in the dermomyotome of developing somites and in migratory muscle progenitors that populate the limb buds. Down-regulation of Pax3 is essential to ignite the myogenic program, including up-regulation of myogenic regulators, Myf-5 and MyoD. MicroRNAs (miRNAs) confer robustness to developmental timing by posttranscriptional repression of genetic programs that are related to previous developmental stages or to alternative cell fates. Here we demonstrate that the muscle-specific miRNAs miR-1 and miR-206 directly target Pax3. Antagomir-mediated inhibition of miR-1/miR-206 led to delayed myogenic differentiation in developing somites, as shown by transient loss of myogenin expression. This correlated with increased Pax3 and was phenocopied using Pax3-specific target protectors. Loss of myogenin after antagomir injection was rescued by Pax3 knockdown using a splice morpholino, suggesting that miR-1/miR-206 control somite myogenesis primarily through interactions with Pax3. Our studies reveal an important role for miR-1/miR-206 in providing precision to the timing of somite myogenesis. We propose that posttranscriptional control of Pax3 downstream of miR-1/miR-206 is required to stabilize myoblast commitment and subsequent differentiation. Given that mutually exclusive expression of miRNAs and their targets is a prevailing theme in development, our findings suggest that miRNA may provide a general mechanism for the unequivocal commitment underlying stem cell differentiation

show abstract

Section: Discussionmentioning

confidence: 99%

MicroRNA regulation of the paired-box transcription factor Pax3 confers robustness to developmental timing of myogenesis

Goljanek‐Whysall¹,

Sweetman²,

Abu‐Elmagd³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

120

121

View full text Add to dashboard Cite

show abstract

“…A recent study also reported miRNA mediated regulation of PAX3. 36 A subset of ARMS is characterized by PAX7-FOXO1 translocation; a recent study has shown that both miR-1 and -206 can potentially regulate PAX7 in skeletal muscle satellite cells. 37 Based on these evidences, we propose that loss of 3 0 UTR of PAX3/PAX7 and /or the downregulation of miR-1 and -206 are oncogenic events in rhabdomyosarcomagenesis ( Figure 7).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma

Sarver

Alamgir

et al. 2012

Laboratory Investigation

105

View full text Add to dashboard Cite

Elevated levels of PAX3 and cell proliferation genes are characteristic features of rhabdomyosarcoma (RMS). We hypothesize that the increased levels of these genes are stabilized due to downregulation of specific miRNAs. In this study, we show that downregulation of miR-1, -206 and -29 stabilizes the expression of PAX3 and CCND2 in both embryonal (ERMS) and alveolar (ARMS) RMS types. Ectopic expression of miR-1 and 206 in JR1, an ERMS cell line, show significant downregulation of PAX3 protein expression, whereas overexpression of these miRNAs in Rh30, an ARMS cell line, did not show any effect in PAX3 protein levels. In ARMS, PAX3 forms a fusion transcript with FOXO1 and the resultant loss of PAX3 3 0 UTR in the fusion transcript indicate an oncogenic mechanism to evade miRNA-mediated regulation of PAX3. Further, we show that miR-1, -206 and -29 can regulate the expression of CCND2, a cell cycle gene. In addition to CCND2, miR-29 also targets E2F7, another cell cycle regulator. Cell function analysis shows that overexpression of miR-29 downregulates the expression of these cell cycle genes, induces partial G1 arrest leading to decreased cell proliferation. Taken together our data suggest that the RMS state is stabilized by the deregulation of multiple miRNAs and their target genes, supporting a tumor suppressor role for these miRNA. KEYWORDS: cell cycle genes; miRNAs; PAX3; regulatory networks; rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a malignant striated muscle tumor that accounts for B3% of all childhood cancers. 1 RMS arises from primitive muscle cells and tumors show varying degrees of skeletal muscle differentiation that serves to define their classification as either embryonal (ERMS) or alveolar (ARMS) types. 2,3 ERMS, the most common type has features of embryonic muscle and are generally associated with favorable prognosis. In contrast, ARMS display poor muscle differentiation and are associated with poor outcomes. 4 Most ARMS cases are characterized by chromosomal translocation t(2;13) or t(1;13) involving genes PAX3-FKHR or PAX7-FKHR, respectively. 5 Regulatory disruptions in growth and differentiation pathways of myogenic precursor cells have been implicated in RMS development. Genes involved with muscle cell differentiation and cell proliferation have been associated with RMS development and metastasis. 6-11 Gene expression profiles comparing PAX-FOXO1-positive ARMS vs translocation-negative ERMS have identified genes relevant to tumorigenic process of ARMS and ERMS. 12 microRNAs (miRNAs) have been implicated in RMS. [13][14][15] miRNAs are small (18-22 nucleotides) evolutionarily conserved, non-coding RNAs that post-transcriptionally regulate gene expression through mRNA degradation, translation inhibition or chromatin-based silencing mechanisms. 16 Each miRNA can potentially regulate hundreds of targets either directly or indirectly. miRNAs have been shown to be deregulated in many types of cancers. 17 As a consequence, miRNAs from tumor tissue have been proposed for use in the diagnosis, classif...

show abstract

“…Myoblasts are characterized by coexpression of Pax3 and Pax7, transcription factors involved in the specification and maintenance of skeletal muscle progenitors. [42][43][44] In our hands, a strong downregulation of Pax3 and Pax7 was observed between D7 and D14, while MyoG expression remains stable and MyoD was upregulated. These data are consistent with previous published studies reporting that Pax7 is rapidly downregulated in cells that commit to terminal differentiation.…”

Section: Cells Cultured In Three Different Conditions (On Sis In Petrimentioning

confidence: 64%

In Vitro Development and Characterization of a Tissue-Engineered Conduit Resembling Esophageal Wall Using Human and Pig Skeletal Myoblast, Oral Epithelial Cells, and Biologic Scaffolds

Poghosyan

Gaujoux

Vanneaux

et al. 2013

Tissue Engineering Part A

View full text Add to dashboard Cite

Introduction: Tissue engineering represents a promising approach for esophageal replacement, considering the complexity and drawbacks of conventional techniques. Aim: To create the components necessary to reconstruct in vitro or in vivo an esophageal wall, we analyzed the feasibility and the optimal conditions of human and pig skeletal myoblast (HSM and PSM) and porcine oral epithelial cell (OEC) culture on biologic scaffolds. Materials and Methods: PSM and HSM were isolated from striated muscle and porcine OECs were extracted from oral mucosa biopsies. Myoblasts were seeded on an acellular scaffold issue from porcine small intestinal submucosa (SIS) and OEC on decellularized human amniotic membrane (HAM). Seeding conditions (cell concentrations [0.5 · 10 6 versus 10 6 cells/cm 2 ] and culture periods [7, 14 and 21 days]), were analyzed using the methyl thiazoltetrazolium assay, quantitative PCR, flow cytometry, and immunohistochemistry. Results: Phenotypic stability was observed after cellular expansion for PSM and HSM (85% and 97% CD56-positive cells, respectively), and OECs (90% AE1/AE3-positive cells). After PSM and HSM seeding, quantities of viable cells were similar whatever the initial cell concentration used and remained stable at all time points. During cell culture on SIS, a decrease of CD56-positive cells was observed (76% and 76% by D7, 56% and 70% by D14, 28% and 60% by D21, for PSM and HSM, respectively). Multilayered surface of a-actin smooth muscle and Desmine-positive cells organized in bundles was seen as soon as D7, with no evidence of cell within the SIS. Myoblasts fusion was observed at D21. Pax3 and Pax7 expression was downregulated and MyoD expression upregulated, at D14.OEC proliferation was observed on HAM with both cell concentrations from D7 to D21. The cell metabolism activity was more important on matrix seeded by 10 6 cells/cm 2 . With 0.5 · 10 6 OEC/cm 2

show abstract

MyoD regulates apoptosis of myoblasts through microRNA-mediated down-regulation of Pax3

Abstract: Suppression of the myogenic transcription factor MyoD is required for maintenance of muscle stem cells.

Cited by 172 publications

References 68 publications

MicroRNA regulation of the paired-box transcription factor Pax3 confers robustness to developmental timing of myogenesis

MicroRNA regulation of the paired-box transcription factor Pax3 confers robustness to developmental timing of myogenesis

Downregulation of microRNAs miR-1, -206 and -29 stabilizes PAX3 and CCND2 expression in rhabdomyosarcoma

In Vitro Development and Characterization of a Tissue-Engineered Conduit Resembling Esophageal Wall Using Human and Pig Skeletal Myoblast, Oral Epithelial Cells, and Biologic Scaffolds

Contact Info

Product

Resources

About