MyoD regulates apoptosis of myoblasts through microRNA-mediated down-regulation of Pax3.
The molecules that regulate the apoptosis cascade are also involved in differentiation and syncytial fusion in skeletal muscle. MyoD is a myogenic transcription factor that plays essential roles in muscle differentiation. We noticed that MyoD(-/-) myoblasts display remarkable resistance to apoptosis by down-regulation of miR-1 (microRNA-1) and miR-206 and by up-regulation of Pax3. This resulted in transcriptional activation of antiapoptotic factors Bcl-2 and Bcl-xL. Forced MyoD expression induces up-regulation of miR-1 and miR-206 and down-regulation of Pax3, Bcl-2, and Bcl-xL along with increased apoptosis in MyoD(-/-) myoblasts. In contrast, MyoD gene knockdown increases cell survival of wild-type myoblasts. The 3' untranslated region of Pax3 mRNA contains two conserved miR-1/miR-206-binding sites, which are required for targeting of these microRNAs (miRNAs). Therefore, these data suggest that MyoD not only regulates terminal differentiation but also apoptosis through miRNA-mediated down-regulation of Pax3. Finally, MyoD, miR-1, and miR-206 are all down-regulated in quiescent satellite cells, which may be required for maintenance of muscle stem cells.
Hirai
Hiroyuki
H
Stem Cell Institute, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Verma
Mayank
M
Watanabe
Shuichi
S
Tastad
Christopher
C
Asakura
Yoko
Y
Asakura
Atsushi
A
D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D015536:Down-Regulation; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017570:MyoD Protein / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology* / Q000502:physiology; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D015533:Transcriptional Activation; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; C540669:Mirn206 microRNA, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C068686:Pax3 protein, mouse; D053148:Caspase 3