Retinoic acid directs cardiac laterality and the expression of early markers of precardiac asymmetry.

Formation of the left/right body axis is a critical early step in embryogenesis. The heart loop is one of the first clearly recognizable morphological asymmetries, and the molecular pathway which dictates this laterality is now beginning to be understood. We report here that the left and right precardiac fields of chick differ in their sensitivity to retinoic acid (RA); while RA applied to the right precardiac field at gastrulation randomizes heart looping, left side treatment induces situs inversus only at high RA concentrations. We identified two extracellular matrix proteins, the heart-specific lectin-associated matrix protein-1 (hLAMP1) and the fibrillin-related protein recognized by the antibody JB3, which are distributed asymmetrically within the precardiac fields at the head process stage. In normal embryos, JB3 expression is enhanced within the right precardiac field, and hLAMP-1 is enriched within the left. RA treatment predictably altered the expression of these proteins in a manner consistent with subsequent heart laterality: RA treatments which randomize heart loop direction also equalized or reversed the left/right JB3 and hLAMP-1 distribution prior to heart tube fusion. The existence of asymmetrically expressed extracellular matrix proteins within precardiac regions suggests that interactions between cardiocytes and their environment may contribute to heart laterality determination and looping.