Anomalous pulmonary venous return is a common form of congenital heart disease though little is known about how the pulmonary veins are normally patterned. Semaphorins are guidance molecules that mediate repulsive cues for axons and blood vessels. We have generated two distinct null alleles of a poorly studied class III semaphorin, sema3d, which results in anomalous pulmonary venous return. Our data suggests that sema3d normally functions as a boundary, constraining migration of nascent pulmonary venous endothelium. The absence of sema3d allows for ectopic migration and patterning of pulmonary venous endothelial cells, leading to anomalous connections. These findings provide an altogether new description of the developmental cause of anomalous pulmonary veins that demands revision of common textbook explanations. In this proposal, we will test the hypothesis that sema3d binds directly to pulmonary venous endothelial cells causing repulsion. We will identify the functional sema3d receptor and the intracellular signaling pathways that result in repulsion, and we will examine how sema3d functionally interacts with Notch and Vegf during angiogenesis.
These studies address the genetic and mechanistic cause of a common form of congenital heart disease in which the pulmonary veins, returning blood from the lungs to the heart, connect to the wrong heart chamber. These studies will identify candidate genes for the cause of this disorder. Our work shows that vascular guidance molecules help to normally pattern the pulmonary veins, and these factors might be useful as therapeutic agents that affect the growth and patterning of blood vessels in diseases such as cancer.
| Artap, Stanley; Manderfield, Lauren J; Smith, Cheryl L et al. (2018) Endocardial Hippo signaling regulates myocardial growth and cardiogenesis. Dev Biol 440:22-30 |
| Pauerstein, Philip T; Tellez, Krissie; Willmarth, Kirk B et al. (2017) A radial axis defined by semaphorin-to-neuropilin signaling controls pancreatic islet morphogenesis. Development 144:3744-3754 |
| Aghajanian, Haig; Cho, Young Kuk; Manderfield, Lauren J et al. (2016) Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor. Nat Commun 7:12038 |
| Singh, Anamika; Ramesh, Sindhu; Cibi, Dasan Mary et al. (2016) Hippo Signaling Mediators Yap and Taz Are Required in the Epicardium for Coronary Vasculature Development. Cell Rep 15:1384-1393 |
| Minchin, James E N; Dahlman, Ingrid; Harvey, Christopher J et al. (2015) Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue. Proc Natl Acad Sci U S A 112:4363-8 |
| Epstein, Jonathan A; Aghajanian, Haig; Singh, Manvendra K (2015) Semaphorin signaling in cardiovascular development. Cell Metab 21:163-173 |
| Aghajanian, Haig; Choi, Connie; Ho, Vivienne C et al. (2014) Semaphorin 3d and semaphorin 3e direct endothelial motility through distinct molecular signaling pathways. J Biol Chem 289:17971-9 |
| Chen, Heidi I; Sharma, Bikram; Akerberg, Brynn N et al. (2014) The sinus venosus contributes to coronary vasculature through VEGFC-stimulated angiogenesis. Development 141:4500-12 |
| Worzfeld, Thomas; Swiercz, Jakub M; Sentürk, Aycan et al. (2014) Genetic dissection of plexin signaling in vivo. Proc Natl Acad Sci U S A 111:2194-9 |
| Degenhardt, Karl; Singh, Manvendra K; Aghajanian, Haig et al. (2013) Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections. Nat Med 19:760-5 |
Showing the most recent 10 out of 11 publications
