INTERROGATING THE ROLES OF SIGNALING CUES DURING ASYMMETRIC MORPHOGENESIS OF THE ZEBRAFISH HEART

Abstract

Vertebrate heart development is driven by an intricate succession of morphogenetic cell movements, the coordination of which requires precise interpretation of signaling cues by heart primordia. Failure to undergo any of the cellular and tissue-level events mediated by signaling molecules results in congenital heart defects, which affect 40,000 American infants each year. Thus, dissecting the links between signaling cues and the cellular movements that control heart development is crucial for understanding the pathogenic mechanism of these malformations.

In zebrafish, the Nodal pathway governs directional cardiac precursor cell (CPC) migration by inducing left-right asymmetries in migration speeds. However, the molecular mechanisms through which this occurs are unknown, and the signals acting in concert with Nodal during this process have not been fully elucidated. Here, using two-photon imaging, we show that Nodal controls CPC migration by inducing left-right asymmetries in the formation of actin-based protrusions in CPCs. We further find that Nodal functions cooperatively with, and independently of, FGF signals during heart tube formation: both pathways act as migratory stimuli for CPCs, but FGF is dispensable for directing heart tube asymmetry, which is governed by the sidedness of Nodal expression in the lateral plate mesoderm. Moreover, aberrant Nodal and FGF signaling perturb the morphogenetic movements underpinning heart tube formation. We also interrogate the roles of Nodal and FGF signals during cardiac looping and chamber expansion: while both signals are required for proper looping chirality, only FGF signals are required for chamber expansion. Together, our data shed insight into how the spatio-temporal dynamics of signaling cues regulate the cellular behaviors underlying organ morphogenesis.