One percent of newborns suffer from congenital heart defects. This statistic highlights the importance of expanding our current understanding of the mechanisms regulating heart morphogenesis. Many heart abnormalities, including defects in outflow tract (OT) and ventricular septation and OT valve defects, can be phenocopied in model organisms by disrupting cardiac neural crest cell (CNCC) development. CNCC delaminate from the dorsal neural tube and migrate into the branchial arches. These cells then migrate along the branchial arch arteries into the OT and form the initial aorticopulminary septum and then differentiate as vascular smooth muscle cells (VSMC). CNCC also contribute heavily to the OT endocardial-cushion (OTC) which gives rise to the OT valves. Wnt proteins are a large family of secreted ligands that regulate numerous cellular processes, including differentiation, proliferation, survival, migration and adhesion. Wnt proteins signal through at least two distinct pathways. The canonical Wnt pathway activates transcription by TCP-family DNA binding proteins. Canonical Wnt signaling is required for the proliferation and survival of CNCC. The non-canonical Wnt pathway activates multiple intracellular effectors, including Rho-family GTPases and Ca2+ dependent Protein Kinase C (PKC) isoforms. There is circumstantial evidence to suggest that non-canonical Wnt signaling regulates the adhesion and migration of CNCC. RhoA and PKC have also been implicated in the differentiation, proliferation and survival of vascular smooth muscle. Since non-canonical Wnt pathway utilizes RhoA and PKC, non-canonical Wnt signaling may influence these processes in CNCC. Finally, non-canonical Wnt signaling inhibits canonical Wnt signaling in multiple contexts. If non-canonical Wnt signaling inhibits the canonical Wnt pathway in CNCC, it may secondarily processes regulated by canonical Wnt signaling such as proliferation and survival. The overarching goal this proposal is to determine if non-canonical Wnt signaling to CNCC is required for OT and OTC development by removing the function of two critical non-canonical Wnt pathway components, Daaml and Fzd2, from CNCC. Experiments will determine if these proteins influence differentiation, proliferation, survival, adhesion, migration and canonical Wnt signaling in CNCC. Experiments described in this proposal will determine if disrupting non-canonical Wnt signaling can contribute to congenital heart defects. This.information may lead to new detection or treatment strategies. ? ? ?
| Cohen, Ethan David; Ihida-Stansbury, Kaori; Lu, Min Min et al. (2009) Wnt signaling regulates smooth muscle precursor development in the mouse lung via a tenascin C/PDGFR pathway. J Clin Invest 119:2538-49 |
