Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2

• Published in: Genes & development 2005-09, Vol.19 (17), p.2066-2077
• Main Authors: Nakagawa, Osamu, Arnold, Michael, Nakagawa, Masayo, Hamada, Hideaki, Shelton, John M, Kusano, Hajime, Harris, Thomas M, Childs, Geoffrey, Campbell, Kevin P, Richardson, James A, Nishino, Ichizo, Olson, Eric N
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Base Sequence; DNA - genetics; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancer Elements, Genetic; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Expression Regulation, Enzymologic; MEF2 Transcription Factors; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; Muscle, Skeletal - embryology; Muscle, Skeletal - enzymology; Muscle, Skeletal - pathology; Myogenic Regulatory Factors; Myopathies, Structural, Congenital - enzymology; Myopathies, Structural, Congenital - etiology; Myopathies, Structural, Congenital - genetics; Myopathies, Structural, Congenital - pathology; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Research Papers; Signal Transduction; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.1338705

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.