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Published online 1 December 2003. doi:10.1083/jcb.200308164
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© The Rockefeller University Press, 0021-9525/2003/12/1033 $8.00
The Journal of Cell Biology, Volume 163, Number 5, 1033-1044

Article

 Aberrant myofibril assembly in tropomodulin1 null mice leads to aborted heart development and embryonic lethality

Kimberly L. Fritz-Six1, Patrick R. Cox2, Robert S. Fischer1, Bisong Xu2, Carol C. Gregorio3, Huda Y. Zoghbi2 and Velia M. Fowler1

1 Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
2 Division of Neuroscience, Department of Pediatrics, and Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030
3 Department of Cell Biology and Anatomy, University of Arizona, Tucson, AZ 85724

Address correspondence to Velia M. Fowler, Department of Cell Biology, CB163, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037. Tel.: (858) 784-8277. Fax: (858) 784-8753. email: velia{at}scripps.edu

Tropomodulin1 (Tmod1) caps thin filament pointed ends in striated muscle, where it controls filament lengths by regulating actin dynamics. Here, we investigated myofibril assembly and heart development in a Tmod1 knockout mouse. In the absence of Tmod1, embryonic development appeared normal up to embryonic day (E) 8.5. By E9.5, heart defects were evident, including aborted development of the myocardium and inability to pump, leading to embryonic lethality by E10.5. Confocal microscopy of hearts of E8–8.5 Tmod1 null embryos revealed structures resembling nascent myofibrils with continuous F-actin staining and periodic dots of {alpha}-actinin, indicating that I-Z-I complexes assembled in the absence of Tmod1. Myomesin, a thick filament component, was also assembled normally along these structures, indicating that thick filament assembly is independent of Tmod1. However, myofibrils did not become striated, and gaps in F-actin staining (H zones) were never observed. We conclude that Tmod1 is required for regulation of actin filament lengths and myofibril maturation; this is critical for heart morphogenesis during embryonic development.

Key Words: actin; tropomodulin; tropomyosin; sarcomere; cardiac muscle

K.L. Fritz-Six and P.R. Cox contributed equally to this work.

Abbreviation used in this paper: Tmod, tropomodulin.


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