title: 3-OST-7 regulates BMP-dependent cardiac contraction.
abstract: 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.
authors: Department of Neurobiology & Anatomy, University of Utah Molecular Medicine Program, Salt Lake City, Utah, United States of America.
authors: Shiela C
authors: SC
authors: Samson
authors: Tania
authors: T
authors: Ferrer
authors: Chuanchau J
authors: CJ
authors: Jou
authors: Frank B
authors: FB
authors: Sachse
authors: Sunita S
authors: SS
authors: Shankaran
authors: Robin M
authors: RM
authors: Shaw
authors: Neil C
authors: NC
authors: Chi
authors: Martin
authors: M
authors: Tristani-Firouzi
authors: H Joseph
authors: HJ
authors: Yost
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D055785:Gene Knockdown Techniques; D024510:Muscle Development / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology; D012518:Sarcomeres / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015238:Sulfotransferases / Q000502:physiology*; D014335:Tropomyosin / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000502:physiology*
chemical_list: D019485:Bone Morphogenetic Proteins; D014335:Tropomyosin; D029961:Zebrafish Proteins; C533646:tpm4a protein, zebrafish; D015238:Sulfotransferases; C000590116:hs3st1l1 protein, zebrafish