Abstract
Notch signaling regulates cell fate selection during development in multiple organs including the lung. Previous studies on the role of Notch in the lung focused mostly on Notch pathway core components or receptor-specific functions. It is unclear, however, how Jagged or Delta-like ligands collectively or individually (Jag1, Jag2, Dll1, Dll4) influence differentiation of airway epithelial progenitors. Using mouse genetic models we show major differences in Jag and Dll in regulation and establishment of cell fate. Jag ligands had a major impact in balancing distinct cell populations in conducting airways, but had no role in the establishment of domains and cellular abundance in the neuroendocrine (NE) microenvironment. Surprisingly, Dll ligands were crucial in restricting cell fate and size of NE bodies and showed an overlapping role with Jag in differentiation of NE-associated secretory (club) cells. These mechanisms may potentially play a role in human conditions that result in aberrant NE differentiation, including NE hyperplasias and cancer.
Highlights
Notch signaling is a major regulator of progenitor cell fate and differentiation during organogenesis, repair-regeneration, and cancer
By in situ hybridization (ISH) analysis none of these ligands were detectable in the airway epithelium prior to or at E11.5
At E14.5 neuroepithelial bodies (NEBs) and pulmonary NE cells (PNEC) were sharply demarcated by Ascl1, and Dll1 and Dll4 transcripts became prominently expressed in NEBs (Figure 1E–F)
Summary
Notch signaling is a major regulator of progenitor cell fate and differentiation during organogenesis, repair-regeneration, and cancer. Four Notch receptors (Notch1–4) and five ligands (Delta-like: Dll, Dll and Dll and Jagged: Jag and Jag2) have been described. Signaling is triggered by ligand-receptor binding through cell-cell interactions, which leads to sequential cleavage of the Notch receptor and binding of its intracellular domain (NICD) to a CSL/RBPJk-activator complex for activation of downstream target genes, such as HEY/HES-family members (Radtke and Raj, 2003; Bray, 2006). Specific Notch ligand-receptor binding in mammalian cells appears to be mostly non-selective or context-dependent
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