title: Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor.
abstract: The four MEF2 transcription factors (MEF2A, -B, -C, and -D) regulate differentiation and calcium-dependent gene expression in muscle cells. We generated mice deficient in MEF2A, the predominant Mef2 gene product expressed in post-natal cardiac muscle. Most mice lacking Mef2a died suddenly within the first week of life and exhibited pronounced dilation of the right ventricle, myofibrillar fragmentation, mitochondrial disorganization and activation of a fetal cardiac gene program. The few Mef2a(-/-) mice that survived to adulthood also showed a deficiency of cardiac mitochondria and susceptibility to sudden death. Paradoxically, MEF2 transcriptional activity, revealed by the expression of a MEF2-dependent transgene, was enhanced in the hearts of Mef2a-mutant mice, reflecting the transcriptional activation of residual MEF2D. These findings reveal specific roles for MEF2A in maintaining appropriate mitochondrial content and cyto-architectural integrity in the post-natal heart and show that other MEF2 isoforms cannot support these activities.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Naya
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
authors.forename: Hai
authors.initials: H
authors.lastname: Wu
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D016757:Death, Sudden, Cardiac; D024202:Electrophoretic Mobility Shift Assay; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008929:Mitochondria, Heart / Q000502:physiology*; D018006:Myogenic Regulatory Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; C578044:Mef2d protein, mouse; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors