title: Wnt/β-catenin signaling enables developmental transitions during valvulogenesis.
abstract: Heart valve development proceeds through coordinated steps by which endocardial cushions (ECs) form thin, elongated and stratified valves. Wnt signaling and its canonical effector β-catenin are proposed to contribute to endocardial-to-mesenchymal transformation (EMT) through postnatal steps of valvulogenesis. However, genetic redundancy and lethality have made it challenging to define specific roles of the canonical Wnt pathway at different stages of valve formation. We developed a transgenic mouse system that provides spatiotemporal inhibition of Wnt/β-catenin signaling by chemically inducible overexpression of Dkk1. Unexpectedly, this approach indicates canonical Wnt signaling is required for EMT in the proximal outflow tract (pOFT) but not atrioventricular canal (AVC) cushions. Furthermore, Wnt indirectly promotes pOFT EMT through its earlier activity in neighboring myocardial cells or their progenitors. Subsequently, Wnt/β-catenin signaling is activated in cushion mesenchymal cells where it supports FGF-driven expansion of ECs and then AVC valve extracellular matrix patterning. Mice lacking Axin2, a negative Wnt regulator, have larger valves, suggesting that accumulating Axin2 in maturing valves represents negative feedback that restrains tissue overgrowth rather than simply reporting Wnt activity. Disruption of these Wnt/β-catenin signaling roles that enable developmental transitions during valvulogenesis could account for common congenital valve defects.
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403-1229, USA Department of Biology, University of Oregon, Eugene, OR 97403-1229, USA.
authors.forename: Fernanda M
authors.initials: FM
authors.lastname: Bosada
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403-1229, USA.
authors.forename: Vidusha
authors.initials: V
authors.lastname: Devasthali
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403-1229, USA Department of Biology, University of Oregon, Eugene, OR 97403-1229, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Jones
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403-1229, USA Department of Biology, University of Oregon, Eugene, OR 97403-1229, USA kryn@uoregon.edu.
authors.forename: Kryn
authors.initials: K
authors.lastname: Stankunas
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000378:metabolism; D019521:Body Patterning / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D054089:Endocardial Cushions / Q000166:cytology / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006351:Heart Valves / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D008822:Mice, Transgenic; D008943:Mitral Valve / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D038081:Organogenesis / Q000187:drug effects / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; D005346:Fibroblast Growth Factors
keywords: Atrioventricular canal; Axin2; Chordae tendineae; Cushion mesenchyme; EMT; Heart valves; Lef1; Mitral valve; Outflow tract; Spongiosa; Tenascin; Versican; Wnt/β-catenin signaling