title: DAAM1 and DAAM2 are co-required for myocardial maturation and sarcomere assembly.
abstract: Wnt ligands regulate heart morphogenesis but the underlying mechanisms remain unclear. Two Formin-related proteins, DAAM1 and 2, were previously found to bind the Wnt effector Disheveled. Here, since DAAM1 and 2 nucleate actin and mediate Wnt-induced cytoskeletal changes, a floxed-allele of Daam1 was used to disrupt its function specifically in the myocardium and investigate Wnt-associated pathways. Homozygous Daam1 conditional knockout (CKO) mice were viable but had misshapen hearts and poor cardiac function. The defects in Daam1 CKO mice were observed by mid-gestation and were associated with a loss of protrusions from cardiomyocytes invading the outflow tract. Further, these mice exhibited noncompaction cardiomyopathy (NCM) and deranged cardiomyocyte polarity. Interestingly, Daam1 CKO mice that were also homozygous for an insertion disrupting Daam2 (DKO) had stronger NCM, severely reduced cardiac function, disrupted sarcomere structure, and increased myocardial proliferation, suggesting that DAAM1 and DAAM2 have redundant functions. While RhoA was unaffected in the hearts of Daam1/2 DKO mice, AKT activity was lower than in controls, raising the issue of whether DAAM1/2 are only mediating Wnt signaling. Daam1-floxed mice were thus bred to Wnt5a null mice to identify genetic interactions. The hearts of Daam1 CKO mice that were also heterozygous for the null allele of Wnt5a had stronger NCM and more severe loss of cardiac function than Daam1 CKO mice, consistent with DAAM1 and Wnt5a acting in a common pathway. However, deleting Daam1 further disrupted Wnt5a homozygous-null hearts, suggesting that DAAM1 also has Wnt5a-independent roles in cardiac development.
authors.affiliation: Mammalian Development Laboratory, National Institute of Genetics, Mishima 411-8540, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Ajima
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Bisson
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Jay-Christian
authors.initials: JC
authors.lastname: Helt
authors.affiliation: Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, NIH, Frederick, MD 21702, USA.
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Nakaya
authors.affiliation: Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Habas
authors.affiliation: Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, NCI, Frederick, MD 21702, USA.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Medicine and Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
authors.affiliation: Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, NIH, Frederick, MD 21702, USA. Electronic address: yamagute@mail.nih.gov.
authors.forename: Terry P
authors.initials: TP
authors.lastname: Yamaguchi
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. Electronic address: ethan_cohen@urmc.rochester.edu.
authors.forename: Ethan David
authors.initials: ED
authors.lastname: Cohen
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006579:Heterozygote; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009024:Morphogenesis; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D020741:rho GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C500366:Daam2 protein, mouse; D008840:Microfilament Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C500365:Daam1 protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein