Investigating the role of Mesp1-mediated mechanisms in directing cell migration and cell fate of distinct cardiac progenitor subpopulations

Abstract

The heart is composed of four cardiac chambers built by distinct progenitor populations. Precise positioning of these subpopulations is critical for normal heart development. These progenitor subpopulations are thus implicated in congenital heart diseases. Elucidation of the molecular mechanisms involved in the specification and migration of these subpopulations will therefore contribute to a better understanding of the etiology of congenital heart diseases and towards improving therapies for cardiac diseases. Cardiac progenitors arise in two waves during gastrulation, both expressing key cardiac transcription factor Mesp1. Subsequently, they migrate to their defined destinations in the embryo. These Mesp1-expressing cells are heterogeneous, and differentially express key transcriptional regulators and signalling pathway components. We wish to uncover the Mesp1-mediated mechanisms that drive the migration of the two distinct subpopulations. We use a combination of mouse embryos (in vivo) and embryonic stem cell-derived (in vitro) models to address our objective. We have uncovered that the heterogeneity in the cardiac progenitor populations extends to the activation of intracellular signalling pathways. This heterogeneity is correlated with their cell fate as progenitors of specific cardiac chambers. Whether this heterogeneity affects their migratory cell behaviour was unknown. We reveal that loss-of-function of the individual downstream pathways leads to distinct migratory phenotypes. We are therefore poised to ask if the priming of a cardiac progenitor population towards a specific cell fate instructs their migratory behaviour, or whether the route they take may restrict their cell fate. In summary, we have begun to reveal differences in the signalling requirements for the migration and cell fate of distinct Mesp1-expressing cardiac progenitor populations.