Efficient blood flow depends on two developmental processes that occur within the atrioventricular junction (AVJ) of the heart: conduction delay, which entrains sequential chamber contraction; and valve formation, which prevents retrograde fluid movement. Defects in either result in severe congenital heart disease; however, little is known about the interplay between these two crucial developmental processes. Here, we show that AVJ conduction delay is locally assigned by the morphogenetic events that initiate valve formation. Our data demonstrate that physical separation from endocardial-derived factors prevents AVJ myocardium from becoming fast conducting. Mechanistically, this physical separation is induced by myocardial-derived factors that support cardiac jelly deposition at the onset of valve formation. These data offer a novel paradigm for conduction patterning, whereby reciprocal myocardial-endocardial interactions coordinate the processes of valve formation with establishment of conduction delay. This, in turn, synchronizes the electrophysiological and structural events necessary for the optimization of blood flow through the developing heart.
Author contributions
Scientific approaches for the manuscript were developed by M.B., R.J.G., P.B.Y. and T.M. Experiments were performed by M.B., P.B.Y., J.D.L. and A.M.N. Data analysis was conducted by M.B., P.B.Y., J.D.L., A.M.N., R.J.G. and T.M. The manuscript was prepared and edited by M.B., P.B.Y., J.D.L. and T.M.
Funding
This work was supported in part by grants from the National Institutes of Health [1K99HL122360 to M.B.; T32 HD 007470 to P.B.Y.; and R01 HL093566, R01 HL112268 and R01 HL078921 to T.M.]. Deposited in PMC for release after 12 months.
