Regulation of vertebrate myotome development by the p38 MAP kinase-MEF2 signaling pathway.
Biochemical and cell culture studies have characterized the myocyte enhancer factor 2 (MEF2) transcriptional regulatory proteins as obligatory partners for the myogenic regulatory factors (MRFs) in the differentiation of myogenic cells in culture. However, the role of MEF2 activation in somitic myogenesis has not been fully characterized. Here, we report a critical interaction between the p38 mitogen-activated protein kinase (p38 MAPK) and MEF2 in the developing somite myotome. We document expression of MEF2A and p38 MAPK proteins in the somite of 9.5 dpc mouse embryos concurrent with Myf 5 protein expression. We also observed that abrogation of p38 MAPK signaling blocks MEF2 activation using a MEF2 transgenic 'sensor' mouse. Inhibition of p38 MAPK signaling concurrently inhibited myogenic differentiation in somite cultures and in embryos in vivo using transplacental injection of a p38 inhibitor (SB203580). Finally, we document that commitment to the myogenic lineage is not appreciably affected by p38 MAPK inhibition since the activation of an early marker of myogenic commitment (Myf 5) occurs normally when p38 MAPK signaling is inhibited. Thus, we present novel evidence indicating a crucial role for p38 MAPK signaling to the MEF2 transcriptional regulators during early mammalian somite development and myotome formation.
de Angelis
Luciana
L
Istituto di Istologia ed Embriologia Generale, Universita di Roma La Sapienza, Via A. Scarpa 14, 00161 Rome, Italy.
Zhao
Jianzhong
J
Andreucci
John J
JJ
Olson
Eric N
EN
Cossu
Giulio
G
McDermott
John C
JC
D000818:Animals; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D047108:Embryonic Development; D005260:Female; D018507:Gene Expression Regulation, Developmental; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000196:embryology*; D018006:Myogenic Regulatory Factors; D018008:Myogenin / Q000235:genetics; D018994:Myosin Light Chains / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; C503801:Myog protein, mouse; D018006:Myogenic Regulatory Factors; D018008:Myogenin; D018994:Myosin Light Chains; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase