PUBLICATION
Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis
- Authors
- Goddard, L.M., Duchemin, A.L., Ramalingan, H., Wu, B., Chen, M., Bamezai, S., Yang, J., Li, L., Morley, M.P., Wang, T., Scherrer-Crosbie, M., Frank, D.B., Engleka, K.A., Jameson, S.C., Morrisey, E.E., Carroll, T.J., Zhou, B., Vermot, J., Kahn, M.L.
- ID
- ZDB-PUB-171024-9
- Date
- 2017
- Source
- Developmental Cell 43(3): 274-289.e5 (Journal)
- Registered Authors
- Duchemin, Anne-Laure, Vermot, Julien
- Keywords
- Klf2, Klf4, Wnt9b, cardiac cushion, endocardium, heart valve development, hemodynamic force
- MeSH Terms
-
- Animals
- Cell Proliferation/physiology
- Endocardium/metabolism*
- Gene Expression Regulation, Developmental/genetics*
- Heart Valves/growth & development*
- Hemodynamics/physiology*
- Kruppel-Like Transcription Factors/metabolism
- Mice, Transgenic
- Organogenesis/physiology
- Signal Transduction/genetics*
- Transcription Factors/genetics
- Wnt Proteins/metabolism
- Zebrafish
- Zebrafish Proteins/metabolism
- PubMed
- 29056552 Full text @ Dev. Cell
Citation
Goddard, L.M., Duchemin, A.L., Ramalingan, H., Wu, B., Chen, M., Bamezai, S., Yang, J., Li, L., Morley, M.P., Wang, T., Scherrer-Crosbie, M., Frank, D.B., Engleka, K.A., Jameson, S.C., Morrisey, E.E., Carroll, T.J., Zhou, B., Vermot, J., Kahn, M.L. (2017) Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis. Developmental Cell. 43(3):274-289.e5.
Abstract
Hemodynamic forces play an essential epigenetic role in heart valve development, but how they do so is not known. Here, we show that the shear-responsive transcription factor KLF2 is required in endocardial cells to regulate the mesenchymal cell responses that remodel cardiac cushions to mature valves. Endocardial Klf2 deficiency results in defective valve formation associated with loss of Wnt9b expression and reduced canonical WNT signaling in neighboring mesenchymal cells, a phenotype reproduced by endocardial-specific loss of Wnt9b. Studies in zebrafish embryos reveal that wnt9b expression is similarly restricted to the endocardial cells overlying the developing heart valves and is dependent upon both hemodynamic shear forces and klf2a expression. These studies identify KLF2-WNT9B signaling as a conserved molecular mechanism by which fluid forces sensed by endothelial cells direct the complex cellular process of heart valve development and suggest that congenital valve defects may arise due to subtle defects in this mechanotransduction pathway.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping