A functional knock-out of titin results in defective myofibril assembly

van der Ven PFM, Bartsch JW, Gautel M, Jockusch H, Furst DO (2000)
JOURNAL OF CELL SCIENCE 113(8): 1405-1414.

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Abstract
Titin, also called connectin, is a giant muscle protein that spans the distance from the sarcomeric Z-disc to the M-band. Titin is thought to direct the assembly of sarcomeres and to maintain sarcomeric integrity by interacting with numerous sarcomeric proteins and providing a mechanical linkage. Since severe defects of such an important molecule are likely to result in embryonic lethality, a cell culture model should offer the best practicable tool to probe the cellular functions of titin. The myofibroblast cell line BHK-21/C13 was described to assemble myofibrils in culture. We have now characterized the sub-line BHK-21-Bi, which bears a small deletion within the titin gene. RNA analysis revealed that in this mutant cell line only a small internal portion of the titin mRNA is deleted. However, western blots, immunofluorescence microscopy and immunoprecipitation experiments showed that only the N-terminal, approx. 100 kDa central Z-disc portion of the 3 MDa titin protein is expressed, due to the homozygous deletion in the gene. Most importantly, in BHK-21-Bi cells the formation of thick myosin filaments and the assembly of myofibrils are impaired, although sarcomeric proteins are expressed. Lack of thick filament formation and of ordered actin-myosin arrays was confirmed by electron microscopy. Myogenisation induced by transfection with MyoD yielded myofibrils only in myotubes formed from wild type and not from mutant cells, ruling out that a principal failure in myogenic commitment of the BHK-21-Bi cells might cause the observed effects. These experiments provide the first direct evidence for the crucial role of titin in both thick filament formation as a molecular ruler and in the coordination of myofibrillogenesis.
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van der Ven PFM, Bartsch JW, Gautel M, Jockusch H, Furst DO. A functional knock-out of titin results in defective myofibril assembly. JOURNAL OF CELL SCIENCE. 2000;113(8):1405-1414.
van der Ven, P. F. M., Bartsch, J. W., Gautel, M., Jockusch, H., & Furst, D. O. (2000). A functional knock-out of titin results in defective myofibril assembly. JOURNAL OF CELL SCIENCE, 113(8), 1405-1414.
van der Ven, P. F. M., Bartsch, J. W., Gautel, M., Jockusch, H., and Furst, D. O. (2000). A functional knock-out of titin results in defective myofibril assembly. JOURNAL OF CELL SCIENCE 113, 1405-1414.
van der Ven, P.F.M., et al., 2000. A functional knock-out of titin results in defective myofibril assembly. JOURNAL OF CELL SCIENCE, 113(8), p 1405-1414.
P.F.M. van der Ven, et al., “A functional knock-out of titin results in defective myofibril assembly”, JOURNAL OF CELL SCIENCE, vol. 113, 2000, pp. 1405-1414.
van der Ven, P.F.M., Bartsch, J.W., Gautel, M., Jockusch, H., Furst, D.O.: A functional knock-out of titin results in defective myofibril assembly. JOURNAL OF CELL SCIENCE. 113, 1405-1414 (2000).
van der Ven, PFM, Bartsch, JW, Gautel, M, Jockusch, Harald, and Furst, DO. “A functional knock-out of titin results in defective myofibril assembly”. JOURNAL OF CELL SCIENCE 113.8 (2000): 1405-1414.
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