Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2.
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.
Nakagawa
Osamu
O
Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. osamu.nakagawa@utsouthwestern.edu
Arnold
Michael
M
Nakagawa
Masayo
M
Hamada
Hideaki
H
Shelton
John M
JM
Kusano
Hajime
H
Harris
Thomas M
TM
Childs
Geoffrey
G
Campbell
Kevin P
KP
Richardson
James A
JA
Nishino
Ichizo
I
Olson
Eric N
EN
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D064326:MEF2 Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000196:embryology / Q000201:enzymology / Q000473:pathology; D018006:Myogenic Regulatory Factors; D020914:Myopathies, Structural, Congenital / Q000201:enzymology* / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C504341:SRPK3 protein, mouse