3-OST-7 regulates BMP-dependent cardiac contraction

• Published in: PLoS biology 2013-12, Vol.11 (12), p.e1001727-e1001727
• Main Authors: Samson, Shiela C, Ferrer, Tania, Jou, Chuanchau J, Sachse, Frank B, Shankaran, Sunita S, Shaw, Robin M, Chi, Neil C, Tristani-Firouzi, Martin, Yost, H Joseph
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Animals; Bone morphogenetic proteins; Bone Morphogenetic Proteins - physiology; Experiments; Gene Knockdown Techniques; Genotype & phenotype; Glycosaminoglycans; Health aspects; Heart; Heart muscle; Heparan sulfate; Medical research; Medicine, Experimental; Morphogenesis; Muscle contraction; Muscle Development - physiology; Myocardial Contraction - physiology; Myocytes, Cardiac - physiology; Physiological aspects; Plasmids; Rodents; Sarcomeres - physiology; Signal Transduction - physiology; Sulfotransferases - physiology; Transcription factors; Tropomyosin - physiology; Zebrafish; Zebrafish Proteins - physiology
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1001727

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.