Myf5 expression in satellite cells and spindles in adult muscle is controlled by separate genetic elements.
The myogenic regulatory factor Myf5 is integral to the initiation and control of skeletal muscle formation. In adult muscle, Myf5 is expressed in satellite cells, stem cells of mature muscle, but not in the myonuclei that sustain the myofibre. Using the Myf5(nlacZ/+) mouse, we now show that Myf5 is also constitutively expressed in muscle spindles-stretch-sensitive mechanoreceptors, while muscle denervation induces extensive reactivation of the Myf5 gene in myonuclei. To identify the elements involved in the regulation of Myf5 in adult muscle, we analysed reporter gene expression in a transgenic bacterial artificial chromosome (BAC) deletion series of the Mrf4/Myf5 locus. A BAC carrying 140 kb upstream of the Myf5 transcription start site was sufficient to drive all aspects of Myf5 expression in adult muscle. In contrast, BACs carrying 88 and 59 kb upstream were unable to drive consistent expression in satellite cells, although expression in muscle spindles and reactivation of the locus in myonuclei were retained. Therefore, as during development, multiple enhancers are required to generate the full expression pattern of Myf5 in the adult. Together, these observations show that elements controlling adult Myf5 expression are genetically separable and possibly distinct from those that control Myf5 during development. These studies are a first step towards identifying cognate transcription factors involved in muscle stem cell regulation.
Zammit
Peter S
PS
Muscle Cell Biology Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, W12 0NN, UK. peter.zammit@csc.mrc.ac.uk
Carvajal
Jaime J
JJ
Golding
Jon P
JP
Morgan
Jennifer E
JE
Summerbell
Dennis
D
Zolnerciks
Joseph
J
Partridge
Terence A
TA
Rigby
Peter W J
PW
Beauchamp
Jonathan R
JR
D000818:Animals; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D046508:Culture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D008465:Mechanoreceptors / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009121:Muscle Denervation; D009124:Muscle Proteins / Q000235:genetics*; D009470:Muscle Spindles / Q000254:growth & development / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D051787:Myogenic Regulatory Factor 5; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*
D004268:DNA-Binding Proteins; D009124:Muscle Proteins; C497418:Myf5 protein, mouse; D051787:Myogenic Regulatory Factor 5; D015534:Trans-Activators