Investigating collective myocardial cell movement during heart tube formation

Project Summary
Organ formation is critically regulated by inter-tissue communication. The architecture of the mature heart
is a result of sequential morphogenetic events, starting with the primitive heart tube, which is the
foundation upon which the rest of the heart is built. The process of building the primitive heart tube starts
with the collective movement of myocardial cells from bilateral locations in the anterior lateral plate
mesoderm to the midline, a process called cardiac fusion which is conserved in all vertebrates. Genetic
analysis has revealed that the adjacent endoderm is critical for these movements. However, the signals
or molecules by which the endoderm communicates to the myocardium remain unknown. Furthermore,
the molecular mechanism by which myocardial cells in vertebrates respond to these signals and
collectively move towards the midline is also poorly understood. To elucidate these mechanisms,
undergraduate and graduate students from the University of Mississippi will take a multi-dimensional
approach examining cardiac fusion at the tissue, molecular, cellular and biomechanical level. We have
found that mutations in the Platelet-derived growth factor receptor alpha (Pdgfra) leads to cardiac fusion
defects in both zebrafish and mice. Myocardial movement appears to occur in response to a localized
source of the PDGF ligand pdgf-aa, which we found is expressed in the endoderm medially adjacent to
pdgfra expression in the myocardium. Furthermore, our preliminary data reveals that disruption of PI3K
signaling in zebrafish also causes cardiac fusion defects. And that myocardial cells exhibit protrusions
and display heterogenous changes in cell shape during cardiac fusion. Together, this data suggests the
hypothesis that paracrine PDGF signals from the endoderm activates Pdgfra-mediated PI3K signaling in
the myocardium to create medial oriented migratory protrusions which create asymmetric biomechanical
tension in the myocardium facilitating medial movement. We will test this hypothesis by using tissue-
specific genetic techniques to determine the tissues in which pdgfra and pdgf-aa function (Aim 1) as well
as determine whether PI3K signaling and migratory protrusions are activated downstream of Pdgfra
(Aim2). Additionally, we will use micro-rheology and micro-laser ablation in combination with pdgfra
mutants to examine the biomechanical properties in the myocardium controlled by PDGF signaling (Aim
3). In summary, these studies are likely to elucidate the molecular mechanisms that underlie how
myocardial cells sense and respond to their local environment and in the long-term identify the
fundamental principles that underlie cardiac morphogenesis in both development and disease.
Furthermore, this proposal will help to establish a research program that intertwines student research
opportunities with the discovery of fundamental molecular mechanisms underlying inter-tissue
communication during organ morphogenesis.

Grant Number: 1R15HD108782-01
NIH Institute/Center: NIH
Principal Investigator: Joshua Bloomekatz