Loss of FilaminC (FLNc) results in severe defects in myogenesis and myotube structure.
FilaminC (FLNc) is the muscle-specific member of a family of actin binding proteins. Although it interacts with many proteins involved in muscular dystrophies, its unique role in muscle is poorly understood. To address this, two models were developed. First, FLNc expression was stably reduced in C2C12 myoblasts by RNA interference. While these cells start differentiation normally, they display defects in differentiation and fusion ability and ultimately form multinucleated "myoballs" rather than maintain elongated morphology. Second, a mouse model carrying a deletion of last 8 exons of Flnc was developed. FLNc-deficient mice die shortly after birth, due to respiratory failure, and have severely reduced birth weights, with fewer muscle fibers and primary myotubes, indicating defects in primary myogenesis. They exhibit variation in fiber size, fibers with centrally located nuclei, and some rounded fibers resembling the in vitro phenotype. The similarity of the phenotype of FLNc-deficient mice to the filamin-interacting TRIO null mice was further confirmed by comparing FLNc-deficient C2C12 cells to TRIO-deficient cells. These data provide the first evidence that FLNc has a crucial role in muscle development and maintenance of muscle structural integrity and suggest the presence of a TRIO-FLNc-dependent pathway in maintaining proper myotube structure.
Dalkilic
I
I
Howard Hughes Medical Institute and Program in Genomics, Children's Hospital, Boston, Massachusetts 02115, USA.
Schienda
J
J
Thompson
T G
TG
Kunkel
L M
LM
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002459:Cell Fusion; D003285:Contractile Proteins / Q000172:deficiency* / Q000235:genetics; D003433:Crosses, Genetic; D005260:Female; D064448:Filamins; D005786:Gene Expression Regulation; D018390:Gene Targeting; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency; D006801:Humans; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000172:deficiency* / Q000235:genetics; D024510:Muscle Development / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000473:pathology*; D018482:Muscle, Skeletal / Q000002:abnormalities / Q000648:ultrastructure; D032446:Myoblasts / Q000166:cytology; D009929:Organ Size; D010641:Phenotype; D010750:Phosphoproteins / Q000172:deficiency; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D020662:Guanine Nucleotide Exchange Factors; D008840:Microfilament Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C490975:Trio protein, mouse; D017346:Protein Serine-Threonine Kinases