FGF6 mediated expansion of a resident subset of cells with SP phenotype in the C2C12 myogenic line.
Fibroblast growth factor 6 (FGF6) is selectively expressed during muscle development and regeneration. We examined its effect on muscle precursor cells (mpc) by forcing stable FGF6 expression in C2C12 cells in vitro. FGF6 produced in genetically engineered mpc was active, inducing strong morphological changes, altering cell adhesion and compromising their ability to differentiate into myotubes. Expression of MyoD and myogenin, but not of Myf5, was abrogated in FGF6 engineered mpc. These effects were reversed by FGF inhibitors. Ectopic expression of MyoD also restored fiber formation indicating that FGF6 interferes with the myogenic differentiation pathway upstream of MyoD. We also report that in the presence of FGF6, the minor (0.5-2%) subpopulation of cells actively excluding Hoechst 33342 in a verapamil-dependent manner (SP phenotype) was increased to 15-20% and the expression of the mdr1a gene (but not mdr1b) was upregulated by 400-fold. Our data establish a previously undescribed link between FGF6--a muscle specific growth factor--and a multidrug resistance gene expressed in stem cells, and suggest a role for FGF6 in the maintenance of a reserve pool of progenitor cells in the skeletal muscle.
Israeli
David
D
Genethon-Centre National de la Recherche Scientifique UMR 8115, 91002 Evry cedex, France.
Benchaouir
Rachid
R
Ziaei
Simindokht
S
Rameau
Philippe
P
Gruszczynski
Carole
C
Peltekian
Elise
E
Danos
Olivier
O
Garcia
Luis
L
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D051522:Fibroblast Growth Factor 6; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; C486115:Fgf6 protein, mouse; D051522:Fibroblast Growth Factor 6; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D005346:Fibroblast Growth Factors; C095122:multidrug resistance protein 3