title: Aberrant myofibril assembly in tropomodulin1 null mice leads to aborted heart development and embryonic lethality.
abstract: 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.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Fritz-Six
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Cox
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fischer
authors.forename: Bisong
authors.initials: B
authors.lastname: Xu
authors.forename: Carol C
authors.initials: CC
authors.lastname: Gregorio
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.forename: Velia M
authors.initials: VM
authors.lastname: Fowler
mesh_terms: D000185:Actinin / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D064211:Connectin; D020964:Embryo Loss; D005314:Embryonic and Fetal Development; D018390:Gene Targeting; D005838:Genotype; D005865:Gestational Age; D006321:Heart / Q000196:embryology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000378:metabolism; D051348:Tropomodulin
chemical_list: D002352:Carrier Proteins; D064211:Connectin; D008840:Microfilament Proteins; D009124:Muscle Proteins; D010456:Peptides, Cyclic; C495829:TMOD1 protein, human; C495831:Tmod1 protein, mouse; D051348:Tropomodulin; D000185:Actinin; C017613:phallacidin