Key result
Knockdown of 3-OST-7 in zebrafish embryos resulted in a specific loss of cardiac ventricular contraction by uncoupling it from normal calcium cycling and electrophysiology through reduced tpm4 expression.
3-OST-7 is identified as a key component of a novel pathway that constrains BMP signaling from ventricular myocytes, coordinating sarcomere assembly and promoting cardiac contractile function.
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No direct clinical application; leaves open whether 3-OST-7 regulates ventricular function in mammals.
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.
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Samson et al. (2013) studied Cardiac development and ventricular contraction. 3-OST-7 knockdown (morpholino) vs. Control (uninjected or control morpholino) was evaluated on Normal ventricular contraction at 48 hours post-fertilization. Knockdown of 3-OST-7 in zebrafish embryos resulted in a specific loss of cardiac ventricular contraction by uncoupling it from normal calcium cycling and electrophysiology through reduced tpm4 expression.
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