Contraction-induced endocardial id2b plays a dual role in regulating myocardial contractility and valve formation

Biomechanical cues play an essential role in sculpting organ formation. Comprehending how cardiac cells perceive and respond to biomechanical forces is a biological process with significant medical implications that remains poorly understood. Here we show that biomechanical forces activate endocardialid2b(inhibitor of DNA binding 2b) expression, thereby promoting cardiac contractility and valve formation. Taking advantage of the unique strengths of zebrafish, particularly the viability of embryos lacking heartbeats, we systematically compared the transcriptomes of hearts with impaired contractility to those of control hearts. This comparison identifiedid2bas a gene sensitive to blood flow. By generating a knockin reporter line, our results unveiled the presence ofid2bin the endocardium, and its expression is sensitive to both pharmacological and genetic perturbations of contraction. Furthermore,id2bloss-of-function resulted in progressive heart malformation and early lethality. Combining RNA-seq analysis, electrophysiology, calcium imaging, and echocardiography, we discovered profound impairment in atrioventricular (AV) valve formation and defective excitation-contraction coupling inid2bmutants. Mechanistically, deletion ofid2breduced AV endocardial cell proliferation and led to a progressive increase in retrograde blood flow. In the myocardium,id2bdirectly interacted with the bHLH componenttcf3b(transcription factor 3b) to restrict its activity. Inactivatingid2bunleashed its inhibition ontcf3b, resulted in enhanced repressor activity oftcf3b, which subsequently suppressed the expression ofnrg1(neuregulin 1), an essential mitogen for heart development. Overall, our findings identifyid2bas an endocardial cell-specific, biomechanical signaling-sensitive gene, which mediates intercellular communications between endocardium and myocardium to sculpt heart morphogenesis and function.