Convergence of Distinct Pathways to Heart Patterning Revealed by the Small Molecule Concentramide and the Mutation Heart-and-soul

Background: One of the earliest steps in heart formation is the generation of two chambers, as cardiogenic cells deployed in the epithelial sheet of mesoderm converge to form the nascent heart tube. What guides this transformation to organotypic form is not known.

Results: We have identified a small molecule, concentramide, and a genetic mutation called heart-and-soul (has) that disrupt heart patterning. Both cause the ventricle to form within the atrium. Here, we show that the has gene encodes PKC lambda. The effect of the has mutation is to disrupt epithelial cell-cell interactions in a broad range of tissues. Concentramide does not disrupt epithelial interactions, but rather shifts the converging heart field rostrally. What is shared between the concentramide and has effects is a reversal of the order of fusion of the anterior and posterior ends of the heart field.

Conclusions: The polarity of cardiac tube assembly is a critical determinant of chamber orientation and is controlled by at least two distinct molecular pathways. Combined chemical/genetic dissection can identify nodal points in development, of special importance in understanding the complex patterning events of organogenesis.