Tbx5-mediated expression of Ca(2+)/calmodulin-dependent protein kinase II is necessary for zebrafish cardiac and pectoral fin morphogenesis

Rothschild, S.C., Easley, C.A. 4th, Francescatto, L., Lister, J.A., Garrity, D.M., and Tombes, R.M.
Developmental Biology   330(1): 175-184 (Journal)
Registered Authors
Garrity, Deborah, Lister, James A., Rothschild, Sarah Chase, Tombes, Robert M.
Tbx5, CaMK-II, Holt-Oram syndrome, Bradycardia, Heart development, Pectoral fins
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism*
  • Embryo, Nonmammalian/metabolism
  • Gene Expression Regulation, Developmental
  • Heart/embryology*
  • Heart/growth & development
  • Mice
  • Molecular Sequence Data
  • Morphogenesis*/genetics
  • NIH 3T3 Cells
  • T-Box Domain Proteins/metabolism*
  • Transfection
  • Zebrafish/embryology*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
19345202 Full text @ Dev. Biol.
Mutations in the T-box transcription factor, TBX5, result in Holt-Oram syndrome (HOS), a human condition in which cardiac development is defective and forelimbs are stunted. Similarly, zebrafish tbx5 morphants and mutants (heartstrings; hst) lack pectoral fins and exhibit a persistently elongated heart that does not undergo chamber looping. Tbx5 is expressed in the developing atrium, ventricle and in pectoral fin fields, but its genetic targets are still being uncovered. In this study, evidence is provided that Tbx5 induces the expression of a specific member of the CaMK-II (the type II multifunctional Ca(2+)/calmodulin dependent protein kinase) family; this CaMK-II is necessary for proper heart and fin development. Morphants of beta2 CaMK-II (camk2b2), but not the beta1 CaMK-II (camk2b1) paralog, exhibit bradycardia, elongated hearts and diminished pectoral fin development. Normal cardiac phenotypes can be restored by ectopic cytosolic CaMK-II expression in tbx5 morphants. Like tbx5, camk2b2 is expressed in the pectoral fin and looping heart, but this expression is diminished in both tbx5 morphant and hst embryos. Conversely, the introduction of excess Tbx5 into zebrafish embryos and mouse fibroblasts doubles CaMK-II expression. We conclude that beta CaMK-II expression and activity are necessary for proper cardiac and limb morphogenesis. These findings not only identify a morphogenic target for Ca(2+) during heart development, but support implied roles for CaMK-II in adult heart remodeling.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes