Translational control offurinaby an RNA regulon is essential for heart morphogenesis and cardiac valve function

Abstract

AbstractHeart development is a complex process, starting from specification of cardiac precursors and formation of a linear tube to gradual progression to a functional beating organ. For normal heart development, many processes, including asymmetric positioning of the heart along the left-right (L/R) axis, cardiac growth, and cardiac valve morphogenesis must be completed successfully. Although heart development has been studied extensively, the mechanisms that control heart morphogenesis and valve formation are not fully understood. The pro-convertase FurinA is a key protein that functions in heart development in many vertebrates including zebrafish. How FurinA activity is regulated during heart development is not known. Through computational analysis of the zebrafish transcriptome, we identified a short sequence and structure RNA motif in a variant transcript of FurinA harbouring a long 3’untranslated region (3’UTR). The alternative 3’UTRfurinaisoform is expressed at embryonic stages preceding organ positioning. Reporter localization and RNA-binding assays show that thefurina3’UTR forms complexes with the conserved RNA-binding protein and translational repressor Ybx1. Conditional mutant zebrafish embryos affectingybx1show premature and increased Furin reporter protein expression, abnormal cardiac morphogenesis and heart looping defects. Our mutantybx1hearts have an expanded atrioventricular canal, abnormal sino-atrial valves and many mutant embryos show retrograde blood flow from the ventricle to the atrium. This is similar to human heart valve regurgitation patients. Our findings show an essential function for the 3’UTR element/Ybx1 regulon in translational repression of FurinA, revealing a new upstream regulatory mechanism that controls embryonic heart development, and demonstrates theybx1mutant as a model to study cardiac valve development and function.