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.
Stem Cell Institute, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Hiroyuki
H
Hirai
Mayank
M
Verma
Shuichi
S
Watanabe
Christopher
C
Tastad
Yoko
Y
Asakura
Atsushi
A
Asakura
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