LEFT-RIGHT PATTERN OF CARDIAC BMP4 MAY DRIVE ASYMMETRY OF THE HEART IN ZEBRAFISH

The first evident break in left-right symmetry of the primitive zebraf ish heart tube is the shift in pattern of BMP4 expression from radiall y symmetric to left-predominant. The midline heart tube then 'jogs' to the left and subsequently loops to the right. We examined 279 mutatio ns, affecting more than 200 genes, and found 21 mutations that perturb this process. Some cause BMP4 to remain radially symmetric. Others ra ndomize the asymmetric BMP4 pattern. Retention of BMP4 symmetry is ass ociated with failure to jog: right-predominance of the BMP4 pattern is associated with reversal of the direction of jogging and looping. Rai sing BMP4 diffusely throughout the heart, via sonic hedgehog injection , or the blocking of its action by injection of a dominant negative BM P4 receptor, prevent directional jogging or looping. The genes crucial to directing cardiac asymmetry include a subset of those needed for p atterning the dorsoventral axis and for notochord and ventral spinal c ord development. Thus, the pattern of cardiac BMP4 appears to be in th e pathway by which the heart interprets lateralizing signals from the midline.