title: Critical roles for multiple formins during cardiac myofibril development and repair.
abstract: Cardiac and skeletal muscle function depends on the proper formation of myofibrils, which are tandem arrays of highly organized actomyosin contractile units called sarcomeres. How the architecture of these colossal molecular assemblages is established during development and maintained over the lifetime of an animal is poorly understood. We investigate the potential roles in myofibril formation and repair of formin proteins, which are encoded by 15 different genes in mammals. Using quantitative real-time PCR analysis, we find that 13 formins are differentially expressed in mouse hearts during postnatal development. Seven formins immunolocalize to sarcomeres in diverse patterns, suggesting that they have a variety of functional roles. Using RNA interference silencing, we find that the formins mDia2, DAAM1, FMNL1, and FMNL2 are required nonredundantly for myofibrillogenesis. Knockdown phenotypes include global loss of myofibril organization and defective sarcomeric ultrastructure. Finally, our analysis reveals an unanticipated requirement specifically for FMNL1 and FMNL2 in the repair of damaged myofibrils. Together our data reveal an unexpectedly large number of formins, with diverse localization patterns and nonredundant roles, functioning in myofibril development and maintenance, and provide the first evidence of actin assembly factors being required to repair myofibrils.
authors.affiliation: Biology Department and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rosado
authors.forename: Cynthia F
authors.initials: CF
authors.lastname: Barber
authors.forename: Cristina
authors.initials: C
authors.lastname: Berciu
authors.forename: Steven
authors.initials: S
authors.lastname: Feldman
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Birren
authors.forename: Daniela
authors.initials: D
authors.lastname: Nicastro
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Goode
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002454:Cell Differentiation; D000080865:Formins; D018507:Gene Expression Regulation, Developmental; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D024510:Muscle Development / Q000235:genetics*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009252:NADPH Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism* / Q000648:ultrastructure; D053778:Thiazolidines / Q000494:pharmacology; D014945:Wound Healing / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; C000592815:FMNL2 protein, mouse; C413382:Fmnl1 protein, mouse; D000080865:Formins; D006576:Heterocyclic Compounds, 4 or More Rings; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D053778:Thiazolidines; C472645:blebbistatin; C508552:Dia2 protein, mouse; D009252:NADPH Dehydrogenase; C500365:Daam1 protein, mouse; D020741:rho GTP-Binding Proteins; C037067:latrunculin A