title: Double homeobox gene, Duxbl, promotes myoblast proliferation and abolishes myoblast differentiation by blocking MyoD transactivation.
abstract: Homeobox genes encode transcription factors that regulate embryonic development programs including organogenesis, axis formation and limb development. Previously, we identified and cloned a mouse double homeobox gene, Duxbl, whose homeodomain exhibits the highest identity (67 %) to human DUX4, a candidate gene of facioscapulohumeral muscular dystrophy (FSHD). Duxbl proteins have been shown to be expressed in elongated myocytes and myotubes of trunk and limb muscles during embryogenesis. In this study, we found that Duxbl maintained low expression levels in various adult muscles. Duxbl proteins were induced to express in activated satellite cells and colocalized with MyoG, a myogenic differentiating marker. Furthermore, Duxbl proteins were not detected in quiescent satellite cells but detected in regenerated myocytes and colocalized with MyoD and MyoG following cardiotoxin-induced muscle injury. Ectopic Duxbl overexpressions in C2C12 myoblast cells promoted cell proliferation through mainly enhancing cyclin D1 and hyper-phosphorylated retinoblastoma protein but reducing p21 expression. However, Duxbl overexpression in C2C12 cells inhibited myogenic differentiation by decreasing MyoD downstream gene expressions, including M-cadherin, MyoG, p21 and cyclin D3 but not MyoD itself. Duxbl overexpressions also promoted cell proliferation but blocked MyoD-induced myogenic conversion in multipotent mesenchymal C3H10T1/2 cells. In addition, results of a luciferase reporter assay suggest that Duxbl negatively regulated MyoG promoter activity through the proximal two E boxes. In conclusion, these results indicate that Duxbl may play a crucial role in myogenesis and postnatal muscle regeneration by activating and proliferating satellite and myoblast cells.
authors.affiliation: Department of Neurology, Chang-Hua Christian Hospital, Changhua, Taiwan, Republic of China.
authors.forename: Shey-Lin
authors.initials: SL
authors.lastname: Wu
authors.forename: Guo-Zili
authors.initials: GZ
authors.lastname: Li
authors.forename: Chin-Yi
authors.initials: CY
authors.lastname: Chou
authors.forename: Ming-Shiun
authors.initials: MS
authors.lastname: Tsai
authors.forename: Yi-Pei
authors.initials: YP
authors.lastname: Chen
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Li
authors.forename: Gan-Guang
authors.initials: GG
authors.lastname: Liou
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Chang
authors.forename: Shen-Liang
authors.initials: SL
authors.lastname: Chen
authors.forename: Sue-Hong
authors.initials: SH
authors.lastname: Wang
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D005455:Fluorescent Antibody Technique; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D024510:Muscle Development; D017570:MyoD Protein / Q000235:genetics* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism*; D018008:Myogenin / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C553465:Duxbl protein, mouse; D018398:Homeodomain Proteins; D017570:MyoD Protein; C503801:Myog protein, mouse; D018008:Myogenin; D012333:RNA, Messenger; D014157:Transcription Factors