A fluorescent sqt RNA reporter localises to dorsal progenitors in early zebrafish embryos ( Gilligan et al., 2011 Gore et al., 2005 Kumari et al., 2013). The 3′UTR element was first identified in squint ( sqt) transcripts. Conditional deletion of Furin in endothelial cells in mouse did not reduce the severity of phenotype, and heart valve malformations in this allele also resulted in embryonic lethality ( Kim et al., 2012), underscoring the importance of Furin during cardiac development.Īlthough the molecular mechanisms underlying transcriptional control of the Nodal pathway have been extensively studied, very few studies have explored regulation of the LR axis by non-coding regions and post-transcriptional regulation ( Minegishi et al., 2021).We found that many Nodal pathway components in zebrafish harbour a short, conserved 3′ untranslated region (3′UTR) motif characterised by a AGCAC sequence motif, followed by a predicted stem and loop structure motif. Furin mutant mice also exhibit impairment of large vessel formation and defects in yolk sac vasculature ( Dupays et al., 2019 Roebroek et al., 1998). In the mouse, deletions in Furin cause embryonic lethality, and the mutants display a range of cardiac morphogenesis defects, including ventral closure, abnormalities of outflow tract and severe heart looping defects. The furina mutant embryos also display abnormal jaw development and 80% of maternal zygotic mutants die owing to lack of inflation of the swim bladder ( Tessadori et al., 2015 Walker et al., 2006 Zhou et al., 2021). Mutations disrupting zebrafish FurinA result in heart looping and trabeculation defects. Studies in zebrafish showed that FurinA is essential for maturation of the Nodal homologue Southpaw (Spaw) and establishes its signalling range in the LPM. The pro-protein convertase FurinA cleaves Nodal and is essential for heart development in many vertebrates ( Beck et al., 2002 Constam and Robertson, 2000). Thus, the furina 3′UTR element/Ybx1 regulon is important for translational repression of FurinA and regulation of heart development. This is similar to observations in humans with heart valve regurgitation. Mutant ybx1 hearts have an expanded atrioventricular canal, abnormal sino-atrial valves and retrograde blood flow from the ventricle to the atrium. Conditional ybx1 mutant embryos show premature and increased Furin reporter expression, abnormal cardiac morphogenesis and looping defects. Reporter localisation and RNA-binding assays show that the furina 3′UTR forms complexes with the conserved RNA-binding translational repressor, Ybx1. Somatic deletions in the furina 3′UTR lead to embryonic left-right patterning defects. The alternative 3′UTR furina isoform is expressed prior to organ positioning. 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). How FurinA activity is regulated during heart development is unknown. The pro-convertase FurinA functions in heart development across vertebrates. The mechanisms controlling heart morphogenesis and valve formation are not fully understood. Heart development is a complex process that requires asymmetric positioning of the heart, cardiac growth and valve morphogenesis.
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