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 pnsperly achieve their size.
The specific aims of this grant are to elucidate the molecular pathways and cellular mechanisms that are required to restrict the size of the heart during development using zebrafish. During the mentored phase of the award, I characterized a mechanism whereby hoxbSb, a downstream effector of RA signaling, non-autonomously restricts atrial cell number from the adjacent forelimb field. These studies helped to provide novel insights into organogenesis and potentially mechanisms which niay underly developmental syndromes affecting both the heart and the forelimb. Despite my initial studies, we still do not understand the nature of the increase in cardiac cells in RA signaling deficient embryos.
In Specific Aim 1, 1 will perform clonal analysis experiments to determine what cell fates may be directly affected by the increase In cardiac cells. Furthermore, we do not understand how downstream effectors of hoxbSb may be acting to restrict atrial cell number.
In Specific Aim 2, 1 will use loss of function approaches to characterize candidate effector genes downstream of hoxbSb that are required to specifically restrict atrial cell fonnatlon. From our initial screen of downstream effectors of RA signaling, we do not yet know of any genes that specifically restrict ventricular cell number.
In Specific Aim 3, 1 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, 1 will characterize novel mutants that can modify the Impact of RA signaling on heart size. Given the many contexts in which RA signaling acts, Including cardiac regeneration, lung branching, stem cell differentiation, and cancer biology, it is likely that my findings will also have a broad range of applications toward human health and the eventual development of therapeutics.
Congenital heart defects are extremely common, occurring in approximately 11n 10 still births and 1 in 100 live births. The information gleaned from this project will allow a greater understanding of normal heart development and potential causes of congenital heart defects.
|Mandal, Amrita; Rydeen, Ariel; Anderson, Jane et al. (2013) Transgenic retinoic acid sensor lines in zebrafish indicate regions of available embryonic retinoic acid. Dev Dyn 242:989-1000|
|Sorrell, Mollie R J; Dohn, Tracy E; D'Aniello, Enrico et al. (2013) Tcf7l1 proteins cell autonomously restrict cardiomyocyte and promote endothelial specification in zebrafish. Dev Biol 380:199-210|
|Dohn, Tracy E; Waxman, Joshua S (2012) Distinct phases of Wnt/ýý-catenin signaling direct cardiomyocyte formation in zebrafish. Dev Biol 361:364-76|