Notch signaling is required for lateral induction of Jagged1 during FGF-induced lens fiber differentiation
| Autor: | Peggy S. Zelenka, Chun Y. Gao, Senthil S. Saravanamuthu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Cellular differentiation
FGF-2 p57Kip2 Epithelium 0302 clinical medicine Serrate-Jagged Proteins Enzyme Inhibitors Insulin-Like Growth Factor I Notch signaling Platelet-Derived Growth Factor 0303 health sciences Receptors Notch Cell Differentiation Cadherins Cell biology Notch proteins Fiber cell Hes3 signaling axis Intercellular Signaling Peptides and Proteins Jagged Lateral induction Microdissection Jag1 Signal Transduction Cell signaling JAG1 MAP Kinase Signaling System Notch signaling pathway Biology Models Biological Article 03 medical and health sciences NICD Lens Crystalline Animals Rats Wistar Molecular Biology Cyclin-Dependent Kinase Inhibitor p57 N-cadherin 030304 developmental biology Notch2 Epidermal Growth Factor Calcium-Binding Proteins Membrane Proteins Cell Biology Lens differentiation Rats Fibroblast Growth Factors Lens fiber cells Lens fiber cell differentiation Amyloid Precursor Protein Secretases 030217 neurology & neurosurgery Biomarkers Jagged-1 Protein Developmental Biology |
| Popis: | Previous studies of the developing lens have shown that Notch signaling regulates differentiation of lens fiber cells by maintaining a proliferating precursor pool in the anterior epithelium. However, whether Notch signaling is further required after the onset of fiber cell differentiation is not clear. This work investigates the role of Notch2 and Jagged1 (Jag1) in secondary fiber cell differentiation using rat lens epithelial explants undergoing FGF-2 dependent differentiation in vitro. FGF induced Jag1 expression and Notch2 signaling (as judged by the appearance of activated Notch2 Intracellular Domain (N2ICD)) within 12–24 h. These changes were correlated with induction of the Notch effector, Hes5, upregulation of N-cadherin (N-cad), and downregulation of E-cadherin (E-cad), a cadherin switch characteristic of fiber cell differentiation. Induction of Jag1 was efficiently blocked by U0126, a specific inhibitor of MAPK/ERK signaling, indicating a requirement for signaling through this pathway downstream of the FGF receptor. Other growth factors that activate MAPK/ERK signaling (EGF, PDGF, IGF) did not induce Jag1. Inhibition of Notch signaling using gamma secretase inhibitors DAPT and L-685,458 or anti-Jag1 antibody markedly decreased FGF-dependent expression of Jag1 demonstrating Notch-dependent lateral induction. In addition, inhibition of Notch signaling reduced expression of N-cad, and the cyclin dependent kinase inhibitor, p57Kip2, indicating a direct role for Notch signaling in secondary fiber cell differentiation. These results demonstrate that Notch-mediated lateral induction of Jag1 is an essential component of FGF-dependent lens fiber cell differentiation. |
| Databáze: | OpenAIRE |
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