Translational control of furina by an RNA regulon is important for left-right patterning, heart morphogenesis and cardiac valve function

Abstract

ABSTRACT Heart development is a complex process that requires asymmetric positioning of the heart, cardiac growth and valve morphogenesis. The mechanisms controlling heart morphogenesis and valve formation are not fully understood. The pro-convertase FurinA functions in heart development across vertebrates. How FurinA activity is regulated during heart development is unknown. Through computational analysis of the zebrafish transcriptome, we identified an RNA motif in a variant FurinA transcript harbouring a long 3′ untranslated region (3′UTR). The alternative 3′UTR furina isoform is expressed prior to organ positioning. Somatic deletions in the furina 3′UTR lead to embryonic left-right patterning defects. Reporter localisation and RNA-binding assays show that the furina 3′UTR forms complexes with the conserved RNA-binding translational repressor, Ybx1. Conditional ybx1 mutant embryos show premature and increased Furin reporter expression, abnormal cardiac morphogenesis and looping defects. Mutant ybx1 hearts have an expanded atrioventricular canal, abnormal sino-atrial valves and retrograde blood flow from the ventricle to the atrium. This is similar to observations in humans with heart valve regurgitation. Thus, the furina 3′UTR element/Ybx1 regulon is important for translational repression of FurinA and regulation of heart development.