Convergence of distinct pathways to heart patterning revealed by the smallmolecule 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 m esoderm converge to form the nascent heart tube. What guides this transform ation 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 ca use the ventricle to form within the atrium. Here, we show that the has gen e encodes PKC lambda. The effect of the has mutation is to disrupt epitheli al cell-cell interactions in a broad range of tissues. Concentramide does n ot disrupt epithelial interactions, but rather shifts the converging heart field rostrally. What is shared between the concentramide and has effects i s a reversal of the order of fusion of the anterior and posterior ends of t he heart field. Conclusions: The polarity of cardiac tube assembly is a critical determinan t of chamber orientation and is controlled by at least two distinct molecul ar pathways. Combined chemical/genetic dissection can identify nodal points in development, of especial importance in understanding the complex patter ning events of organogenesis.