The long-term goal of our work is to reduce the enormous public health burden caused by heart diseases, both congenital and adult, through a better understanding of vertebrate cardiac progenitor cell biology. Defects in a recently-characterized population of cardiac progenitor cells, the secondary heart field (SHF), have been shown to cause conotruncal malformations in avian and mouse species suggesting that, by analogy, human congenital heart defects can arise from defects in SHF. Currently, SHF research is conducted exclusively in avian and mouse model systems. We provide preliminary evidence that the SHF is conserved in zebrafish, a model organism with unique attributes that will undoubtedly complement studies in higher vertebrates. Specifically, we have demonstrated that a protein required for transforming growth factor ? (TGF?) signaling, latent TGF? binding protein 3 (LTBP3), not only marks the zebrafish SHF, but is also required for the contributions made by SHF progenitors to the embryonic heart. As a result, embryos devoid of LTBP3 transcripts exhibit significant reductions in ventricular lineages (cardiomyocytes and endocardial cells), outflow tract smooth muscle, and aortic arch angioblasts and arteries. The proposed experiments are designed to test the hypotheses that LTBP3+ cells represent the functional equivalent of the SHF, that TGF? signaling is required for SHF development, and that LTBP3 function is genetically downstream of fgf8, an archetypal SHF gene in higher vertebrates. In the long run, these studies will potentially highlight novel genetic causes of human congenital heart disease as well as illuminate potential therapeutic targets for directed differentiation of resident or embryonic cardiac progenitor cells for use in regenerative therapies.
Congenital cardiovascular defects are the number one cause of newborn death in the Western world. The experiments in this grant application are designed to better understand the genetic causes of these defects. In the long run, we hope to reduce the morbidity and mortality resulting from congenital cardiovascular diseases.
|Paffett-Lugassy, Noelle; Singh, Reena; Nevis, Kathleen R et al. (2013) Heart field origin of great vessel precursors relies on nkx2.5-mediated vasculogenesis. Nat Cell Biol 15:1362-9|
|Nevis, Kathleen; Obregon, Pablo; Walsh, Conor et al. (2013) Tbx1 is required for second heart field proliferation in zebrafish. Dev Dyn 242:550-9|
|Zhou, Yong; Cashman, Timothy J; Nevis, Kathleen R et al. (2011) Latent TGF-* binding protein 3 identifies a second heart field in zebrafish. Nature 474:645-8|