title: Disheveled mediated planar cell polarity signaling is required in the second heart field lineage for outflow tract morphogenesis.
abstract: Disheveled (Dvl) is a key regulator of both the canonical Wnt and the planar cell polarity (PCP) pathway. Previous genetic studies in mice indicated that outflow tract (OFT) formation requires Dvl1 and 2, but it was unclear which pathway was involved and whether Dvl1/2-mediated signaling was required in the second heart field (SHF) or the cardiac neural crest (CNC) lineage, both of which are critical for OFT development. In this study, we used Dvl1/2 null mice and a set of Dvl2 BAC transgenes that function in a pathway-specific fashion to demonstrate that Dvl1/2-mediated PCP signaling is essential for OFT formation. Lineage-specific gene-ablation further indicated that Dvl1/2 function is dispensable in the CNC, but required in the SHF for OFT lengthening to promote cardiac looping. Mutating the core PCP gene Vangl2 and non-canonical Wnt gene Wnt5a recapitulated the OFT morphogenesis defects observed in Dvl1/2 mutants. Consistent with genetic interaction studies suggesting that Wnt5a signals through the PCP pathway, Dvl1/2 and Wnt5a mutants display aberrant cell packing and defective actin polymerization and filopodia formation specifically in SHF cells in the caudal splanchnic mesoderm (SpM), where Wnt5a and Dvl2 are co-expressed specifically. Our results reveal a critical role of PCP signaling in the SHF during early OFT lengthening and cardiac looping and suggest that a Wnt5a→ Dvl PCP signaling cascade may regulate actin polymerization and protrusive cell behavior in the caudal SpM to promote SHF deployment, OFT lengthening and cardiac looping.
authors: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 1918 University Blvd., Birmingham, AL 35294, UK.
authors: Tanvi
authors: T
authors: Sinha
authors: Bing
authors: B
authors: Wang
authors: Sylvia
authors: S
authors: Evans
authors: Anthony
authors: A
authors: Wynshaw-Boris
authors: Jianbo
authors: J
authors: Wang
mesh_terms: D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D016764:Cell Polarity / Q000502:physiology*; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D000072261:Dishevelled Proteins; D006321:Heart / Q000196:embryology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology*; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism*; D058105:Polymerization; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D019076:Transgenes / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics; D000071818:Wnt-5a Protein
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; C000606582:Dvl2 protein, mouse; C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse