3-OST-7 Regulates BMP-Dependent Cardiac Contraction

The 3-o-sulfotransferase (3-ost) family catalyzes rare modifications of glycosaminoglycan chains on heparan sulfate proteoglycans,yet their biological functions are largely unknown. knockdown of 3-ost-7 in zebrafish uncouples cardiac ventricular contraction from normal calcium cycling and electrophysiology by reducing tropomyosin4 (tpm4) expression. normal 3-ost-7 activity prevents the expansion of bmp signaling into ventricular myocytes,and ectopic activation of bmp mimics the ventricular noncontraction phenotype seen in 3-ost-7 depleted embryos. in 3-ost-7 morphants,ventricular contraction can be rescued by overexpression of tropomyosin tpm4 but not by troponin tnnt2,indicating that tpm4 serves as a lynchpin for ventricular sarcomere organization downstream of 3-ost-7. contraction can be rescued by expression of 3-ost-7 in endocardium,or by genetic loss of bmp4. strikingly,bmp misregulation seen in 3-ost-7 morphants also occurs in multiple cardiac noncontraction models,including potassium voltage-gated channel gene,kcnh2,affected in romano-ward syndrome and long-qt syndrome,and cardiac troponin t gene,tnnt2,affected in human cardiomyopathies. together these results reveal 3-ost-7 as a key component of a novel pathway that constrains bmp signaling from ventricular myocytes,coordinates sarcomere assembly,and promotes cardiac contractile function. © 2013 samson et al.