3-OST-7 regulates BMP-dependent cardiac contraction
- Authors
- Samson, S.C., Ferrer, T., Jou, C.J., Sachse, F.B., Shankaran, S.S., Shaw, R.M., Chi, N.C., Tristani-Firouzi, M., and Yost, H.J.
- ID
- ZDB-PUB-140127-25
- Date
- 2013
- Source
- PLoS Biology 11(12): e1001727 (Journal)
- Registered Authors
- Chi, Neil C., Shankaran, Sunita Sathy, Yost, H. Joseph
- Keywords
- Embryos, Cardiac ventricles, Heart, BMP signaling, Muscle contraction, Myocardium, Zebrafish, Cardiac atria
- MeSH Terms
-
- Action Potentials/physiology
- Animals
- Bone Morphogenetic Proteins/physiology*
- Gene Knockdown Techniques
- Muscle Development/physiology
- Myocardial Contraction/physiology*
- Myocytes, Cardiac/physiology
- Sarcomeres/physiology
- Signal Transduction/physiology
- Sulfotransferases/physiology*
- Tropomyosin/physiology
- Zebrafish
- Zebrafish Proteins/physiology*
- PubMed
- 24311987 Full text @ PLoS Biol.
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.