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A zebrafish model of heart valve regurgitation reveals key role for translational control of Furina.

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Abstract:
Heart development is a complex process, starting from specification of cardiac precursors, 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.  The pro-convertase FurinA is a key protein that functions during heart development. Through computational analysis of the zebrafish transcriptome, we identified a short sequence and structure RNA motif in a variant 3’UTR transcript of FurinA. The alternative 3’UTR furina isoform is expressed at embryonic stages preceding organ positioning. Reporter localization and RNA-binding assays show that thefurina 3'UTR forms complexes with the RNA-binding protein and translational repressor Ybx1. Consistently, ybx1 mutant zebrafish embryos show premature and increased Furin reporter protein expression, abnormal cardiac morphogenesis and looping defects. Mutant ybx1 hearts have 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 and reveal a new upstream regulatory mechanism that controls heart development and function.  

About the speaker:
Karuna Sampath is a Professor of Biomedicine, University of Warwick. Following her doctoral training at Indiana State University, USA with Gary Stuart she did brief post-doctoral stints with Christopher Wright at Vanderbilt University, Nashville, USA (1995-1996), and Vladimir Korzh at the Institute of Molecular Agrobiology, Singapore (1997-1998). She was a visiting scientist in Anne Ephrussi's lab at EMBL in 1999, and started her independent programme in 2000 as a fellow at the Institute of Molecular Agrobiology, Singapore. She was a group leader at Temasek Life Sciences Laboratory, National University of Singapore from 2002-2013. In 2014, the Sampath lab re-located to the University of Warwick, and the group is now located in the new IBRB at Warwick. Karuna Sampath served on the International Zebrafish society (IZFS) (2019-2022) and currently serves on the board of the European Zebrafish society (EZS). Sampath mentors early career researchers for writing Science spotlight – technical reports for the IZFS newsletter. She is an Associate Editor for the GSA journal GENETICS, and serves on the Editorial Board of the Journal of Molecular and Cell Biology.

https://warwick.ac.uk/fac/sci/med/staff/ksampath/
 

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