Abstract
Myocyte enhancer factor 2 (MEF2) plays essential roles in transcriptional control of muscle development. However, signaling pathways acting downstream of MEF2 are largely unknown. Here, we performed a microarray analysis using Mef2c-null mouse embryos and identified a novel MEF2-regulated gene encoding a muscle-specific protein kinase, Srpk3, belonging to the serine arginine protein kinase (SRPK) family, which phosphorylates serine/arginine repeat-containing proteins. The Srpk3 gene is specifically expressed in the heart and skeletal muscle from embryogenesis to adulthood and is controlled by a muscle-specific enhancer directly regulated by MEF2. Srpk3-null mice display a new entity of type 2 fiber-specific myopathy with a marked increase in centrally placed nuclei; while transgenic mice overexpressing Srpk3 in skeletal muscle show severe myofiber degeneration and early lethality. We conclude that normal muscle growth and homeostasis require MEF2-dependent signaling by Srpk3.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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DNA / genetics
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enhancer Elements, Genetic
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Gene Expression Profiling
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Gene Expression Regulation, Developmental
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Gene Expression Regulation, Enzymologic
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MEF2 Transcription Factors
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Molecular Sequence Data
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Muscle, Skeletal / embryology
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Muscle, Skeletal / enzymology
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Muscle, Skeletal / pathology
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Myogenic Regulatory Factors
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Myopathies, Structural, Congenital / enzymology*
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Myopathies, Structural, Congenital / etiology
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Myopathies, Structural, Congenital / genetics*
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Myopathies, Structural, Congenital / pathology
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Protein Serine-Threonine Kinases / deficiency*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
Substances
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DNA-Binding Proteins
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MEF2 Transcription Factors
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Mef2c protein, mouse
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Myogenic Regulatory Factors
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Transcription Factors
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DNA
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Protein Serine-Threonine Kinases
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SRPK3 protein, mouse