Bone Morphogenetic Protein 2 Signaling Negatively Modulates Lymphatic Development in Vertebrate Embryos
- Authors
- Dunworth, W.P., Cardona-Costa, J., Cagavi, E., Kim, J.D., Fischer, J.C., Meadows, S., Wang, Y., Cleaver, O., Qyang, Y., Ober, E.A., and Jin, S.W.
- ID
- ZDB-PUB-131115-4
- Date
- 2014
- Source
- Circulation research 114(1): 56-66 (Journal)
- Registered Authors
- Cardona-Costa, Jose, Dunworth, William, Fischer, Johanna, Jin, Suk-Won, Kim, Jun-Dae, Ober, Elke
- Keywords
- BMP2, Lymphangiogenesis, PROX1, SMAD, developmental biology, lymphatic capillary, miRNA, microRNA, signaling pathways, vertebrate development
- MeSH Terms
-
- Animals
- Bone Morphogenetic Protein 2/genetics
- Bone Morphogenetic Protein 2/metabolism*
- Cell Differentiation
- Cell Line
- Embryoid Bodies/cytology
- Embryoid Bodies/metabolism
- Endothelial Cells/cytology
- Endothelial Cells/metabolism
- Endothelium, Lymphatic/embryology*
- Endothelium, Lymphatic/metabolism*
- Gene Expression Regulation, Developmental
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Humans
- Lymphatic Vessels/embryology
- Lymphatic Vessels/metabolism
- Mice
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Signal Transduction*
- Smad Proteins/metabolism
- Transcription, Genetic
- Tumor Suppressor Proteins/genetics
- Tumor Suppressor Proteins/metabolism
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 24122719 Full text @ Circ. Res.
Rationale: The emergence of lymphatic endothelial cells (LECs) appears to be highly regulated during development. While several factors that promote the differentiation of LECs in embryonic development have been identified, those that negatively regulate this process are largely unknown.
Objective: To delineate the role of BMP2 signaling on lymphatic development.
Methods and Results: BMP2 signaling negatively regulates the formation of LECs. Developing LECs lack any detectable BMP signaling activity in both zebrafish and mouse embryos, and excess BMP2 signaling in zebrafish embryos and mouse embryonic stem (ES) cell-derived embryoid bodies (EBs) substantially decrease the emergence of LECs. Mechanistically, BMP2 signaling induces expression of miR-31 and miR-181a in a SMAD-dependent mechanism, which in turn, result attenuated expression of PROX1 during development.
Conclusions: Our data identify BMP2 as a key negative regulator for the emergence of the lymphatic lineage during vertebrate development.