Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/13306
Título
NOTCH Activation Promotes Valve Formation by Regulating the Endocardial Secretome.
Autor(es)
Torregrosa-Carrión, Rebeca | Luna-Zurita, Luis CNIC | Garcia-Marques, Fernando CNIC | D'Amato, Gaetano CNIC | Piñeiro-Sabarís, Rebeca | Bonzon-Kulichenko, Elena CNIC | Vazquez, Jesus CNIC | de la Pompa, Jose Luis CNIC
Fecha de publicación
2019-09
Cita
Mol Cell Proteomics. 2019; 18(9):1782-95
Idioma
Inglés
Tipo de documento
journal article
Resumen
The endocardium is a specialized endothelium that lines the inner surface of the heart. Functional studies in mice and zebrafish have established that the endocardium is a source of instructive signals for the development of cardiac structures, including the heart valves and chambers. Here, we characterized the NOTCH-dependent endocardial secretome by manipulating NOTCH activity in mouse embryonic endocardial cells (MEEC) followed by mass spectrometry-based proteomics. We profiled different sets of soluble factors whose secretion not only responds to NOTCH activation but also shows differential ligand specificity, suggesting that ligand-specific inputs may regulate the expression of secreted proteins involved in different cardiac development processes. NOTCH signaling activation correlates with a transforming growth factor-β2 (TGFβ2)-rich secretome and the delivery of paracrine signals involved in focal adhesion and extracellular matrix (ECM) deposition and remodeling. In contrast, NOTCH inhibition is accompanied by the up-regulation of specific semaphorins that may modulate cell migration. The secretome protein expression data showed a good correlation with gene profiling of RNA expression in embryonic endocardial cells. Additional characterization by in situ hybridization in mouse embryos revealed expression of various NOTCH candidate effector genes (Tgfβ2, Loxl2, Ptx3, Timp3, Fbln2, and Dcn) in heart valve endocardium and/or mesenchyme. Validating these results, mice with conditional Dll4 or Jag1 loss-of-function mutations showed gene expression alterations similar to those observed at the protein level in vitro These results provide the first description of the NOTCH-dependent endocardial secretome and validate MEEC as a tool for assaying the endocardial secretome response to a variety of stimuli and the potential use of this system for drug screening.
MESH
Adaptor Proteins, Signal Transducing | Animals | Benzazepines | Calcium-Binding Proteins | Cells, Cultured | Endocardium | Extracellular Matrix | Gene Expression Regulation, Neoplastic | Heart Valves | Intercellular Signaling Peptides and Proteins | Jagged-1 Protein | Mice, Mutant Strains | Receptor, Notch1 | Receptors, Notch | Reproducibility of Results
Versión en línea
DOI
Aparece en las colecciones
Ficheros en el ítem
![Acceso Abierto Acceso Abierto](/themes/Mirage2/images/openAccess.png)
- Nombre:
- NOTCHActivationPromotesValve_2 ...
- Tamaño:
- 4.450Mb
- Formato:
- Descripción:
- Artículo
![Acceso Abierto Acceso Abierto](/themes/Mirage2/images/openAccess.png)
- Nombre:
- NOTCHActivationPromotesValve_2 ...
- Tamaño:
- 20.67Mb
- Formato:
- Desconocido
- Descripción:
- Additional data file