UC San Diego

The rhythmic contraction of the heart depends upon the conductive properties of a small population of highly specialized cardiomyocytes, known as pacemaker cells. In the early embryonic heart, pacemaker cells reside in a ring-like pattern at the venous pole of the atrial chamber, in a region known as the inflow tract (IFT). While the gene regulatory networks that contribute to pacemaker cell differentiation have been previously investigated, we do not fully understand the upstream signaling landscape that defines the dimensions of the IFT. Our analyses in zebrafish suggest an essential role for Bmp signaling in promoting the formation of an appropriate number of IFT cardiomyocytes. Diminished Bmp signaling activity in alk8 mutants results in a substantial reduction of the number of IFT cells. Oppositely, heightened levels of Bmp signaling in chordin mutants leads to an increased number of IFT cells. In both alk8 and chordin mutants, altered numbers of IFT cells are evident within the primitive heart tube, indicating that Bmp signaling impacts IFT development prior to heart tube formation. Indeed, treatment with DMH1, a pharmacological antagonist of Bmp signaling, during gastrulation results in a significant reduction of IFT cell number, but treatment with DMH1 during early somitogenesis or during heart tube formation does not alter the number of IFT cells. Intriguingly, pharmacological inhibition of Wnt signaling during IFT cell differentiation suppresses the enlargement of the IFT in chordin mutants, implying that Wnt signaling acts downstream of Bmp signaling during IFT development. Together, these data suggest a model in which Bmp signaling acts during IFT progenitor specification, upstream of Wnt-directed IFT differentiation, to produce an appropriate number of IFT cardiomyocytes.