Abstract:

Heart 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’UTR furina isoform is expressed at embryonic stages preceding organ positioning. Reporter localization and RNA-binding assays show that the furina 3’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. Mutant ybx1 hearts have an expanded atrioventricular canal, abnormal sino-atrial valves and mutant embryos show retrograde blood flow from the ventricle to the atrium. This is similar to human heart valve regurgitation patients. Our findings show that the 3’UTR element/Ybx1 regulon plays a key role in translational repression of FurinA, revealing a new upstream regulatory mechanism during embryonic heart development, and demonstrates the ybx1mutant as a model to study cardiac valve development and function.

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