This project addresses signaling processes during formation of the aorta and pulmonary trunk, and then in the maturation and maintenance of these vessels. A greater understanding of these processes might lead to diagnostic or therapeutic opportunities for malformations that occur when these processes go awry. We have undertaken neural crest-specific disruption of the type II TGFb receptor gene (Tgfbr2) in mice, to address the role of TGFb signaling in the formation and maturation of the outflow tract vessels of the developing heart. Mutant embryos have persistent truncus arteriosus (PTA) and interrupted aortic arch (IAA- B);later in gestation, the elastic matrix of the neural crest-derived vessel wall of the ductus arteriosus becomes disorganized, leading to vessel wall dilation (aneurysm). The central premise to explain these defects is that the behavior of neural crest cells is dictated by local signaling events, that neural crest cells respond directly to these signals, and that TGFb is one such signal.
Specific Aim 1 : To identify mechanisms by which absence of TGFb signaling in neural crest cells results in PTA. In this Aim, we will identify and characterize the role of genes that are misregulated in neural crest- derived smooth muscle cells;we will also address the requirement for Smad-dependent signaling pathways downstream of the TGFb receptor.
Specific Aim 2 : To address the role of retinoic acid and RA receptors in the formation of the A/P septum, and the potential convergence of this pathway with TGFb signaling pathways. Mutation of retinoic acid receptor genes leads to a virtually identical PTA defect as in Tgfbr2 mutants. We will define the tissue in which retinoic acid signaling occurs, and address the convergence of RA and TGFb signaling pathways in the process of outflow tract septation.
Specific Aim 3 : To address the role of TGFb signaling in vessel wall maturation. In this Aim, we will study the onset of vascular wall deformation, address the extent to which TGFb signal transduction is required in mesodermally-derived vs. neural crest-derived smooth muscle and resolve whether vessel dilation results directly or indirectly from a mechanically impaired vessel wall.
