Congenital heart defects are extremely common, occuring in approximately 1 in 10 still births and 1 in 100 live births. During development, a variety of signals are coordinated that allow an organ to attain its proper size, which is required for its normal function. In vertebrate heart development, several pathways are known to promote induction and growth of the heart, while few pathways are known to restrict the size of the heart. My long-term goal is to understand how organs properly achieve their size.
The specific aims of this grant are to elucidate the molecular pathways that are required to restrict the size of the heart during development using zebrafish. In the Yelon lab, we have found that retinoic acid (RA) signaling is required to restrict the formation of both atrial and ventricular cells through independent cellular mechanisms. However, we do not yet understand the downstream effectors of RA signaling involved in limiting the number of cardiac cells.
In Specific Aim 1, I will use mosaic analysis and fate mapping to determine which cells must receive RA signaling in order to restrict the numbers of atrial and ventricular cells. In a screen for downstream effectors of RA signaling, I have found that HoxbSb is required to specifically restrict atrial cell formation.
In Specific Aim 2, I will use mosaic analysis and fate mapping to characterize the cellular mechanisms through which HoxbSb limits the amount of atrial cells. We do not know any genes involved in specifically restricting ventricular cell number.
In Specific Aim 3, I will use loss of function approaches to identify downstream effectors of RA signaling specifically required to limit ventricular cell number. It is likely other signaling pathways besides RA signaling are involved in restricting cardiac cell formation.
In Specific Aim 4, I propose a mutagenesis screen to identify additional genes required to restrict the number of cardiac cells and/or modify with the impact of RA signaling. The information gleaned from these experiments will allow a greater understanding of normal heart development and potential causes of congenital heart defects. However, given the many contexts in which RA signaling acts, including cardiac regeneration, lung branching, stem cell differentiation, and cancer biology, it is likely that the findings will also have a broad range of applications toward human health and the eventual development of therapeutics.
| Waxman, Joshua S; Yelon, Deborah (2011) Zebrafish retinoic acid receptors function as context-dependent transcriptional activators. Dev Biol 352:128-40 |
| Feng, L; Hernandez, R E; Waxman, J S et al. (2010) Dhrs3a regulates retinoic acid biosynthesis through a feedback inhibition mechanism. Dev Biol 338:1-14 |
| Waxman, Joshua S; Yelon, Deborah (2009) Increased Hox activity mimics the teratogenic effects of excess retinoic acid signaling. Dev Dyn 238:1207-13 |
| Waxman, Joshua S; Keegan, Brian R; Roberts, Richard W et al. (2008) Hoxb5b acts downstream of retinoic acid signaling in the forelimb field to restrict heart field potential in zebrafish. Dev Cell 15:923-34 |
