title: Inhibition of Diaphanous Formin Signaling In Vivo Impairs Cardiovascular Development and Alters Smooth Muscle Cell Phenotype.
abstract: OBJECTIVE
  We and others have previously shown that RhoA-dependent stimulation of myocardin-related transcription factor nuclear localization promotes smooth muscle cell (SMC) marker gene expression. The goal of this study was to provide direct in vivo evidence that actin polymerization by the diaphanous-related formins contributes to the regulation of SMC differentiation and phenotype.
  
  
  RESULTS
  Conditional Cre-based genetic approaches were used to overexpress a well-characterized dominant-negative variant of mDia1 (DNmDia) in SMC. DNmDia expression in SM22-expressing cells resulted in embryonic and perinatal lethality in ≈20% of mice because of defects in myocardial development and SMC investment of peripheral vessels. Although most DNmDia(+)/SM22Cre(+) mice exhibited no overt phenotype, the re-expression of SMC differentiation marker gene expression that occurs after carotid artery ligation was delayed, and this effect was accompanied by a significant decrease in myocardin-related transcription factor-A nuclear localization. Interestingly, neointima growth was inhibited by expression of DNmDia in SMC and this was likely because of a defect in directional SMC migration and not to defects in SMC proliferation or survival. Finally, by using the tamoxifen-inducible SM MHC-CreER(T2) line, we showed that SMC-specific induction of DNmDia in adult mice decreased SMC marker gene expression.
  
  
  CONCLUSIONS
  Our demonstration that diaphanous-related formin signaling plays a role in heart and vascular development and the maintenance of SMC phenotype provides important new evidence that Rho/actin/myocardin-related transcription factor signaling plays a critical role in cardiovascular function.
authors.affiliation: From the Department of Pathology, University of North Carolina, Chapel Hill.
authors.forename: Laura
authors.initials: L
authors.lastname: Weise-Cross
authors.affiliation: From the Department of Pathology, University of North Carolina, Chapel Hill.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Taylor
authors.affiliation: From the Department of Pathology, University of North Carolina, Chapel Hill. cmack@med.unc.edu.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Mack
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D000080865:Formins; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D008026:Ligation; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D024510:Muscle Development; D009124:Muscle Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000196:embryology / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D058105:Polymerization; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D057772:Vascular System Injuries
chemical_list: D000199:Actins; D002352:Carrier Proteins; C491464:Diap1 protein, mouse; D000080865:Formins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse
keywords: carotid arteries; mDia2 protein; mouse; myocardin; phenotype; smooth muscle