Notch1 and Jagged1 expression by the developing pulmonary vasculature

Abstract

The molecular mechanisms of pulmonary vascular development are poorly understood. Cell-specific developmental pathways are influenced by cell-cell signaling. Notch signaling molecules are highly conserved receptors active in many cell-fate determination systems. Recent observations of Notch molecules and a Notch ligand, Jagged1, suggest their importance in vascular morphogenesis, and particularly pulmonary vascular development. We performed a systematic evaluation of Notch1/Jagged1 gene and protein expression in the developing mouse lung from embryonic day 11 until adulthood by using quantitative PCR, immunofluorescence, and electron microscopic analysis. mRNA transcripts for Notch1-4 and Jagged1 increased progressively from early to later lung development, accompanied by a simultaneous rise in endothelial cell-specific gene expression, a pattern not seen in other organs. Notch1 mRNA was identified on both epithelial and mesenchymal structures of the embryonic lung. Immunofluorescence staining revealed the progressive acquisition of Notch1 and Jagged1 proteins by the emerging endothelium. Notch1 and Jagged1 were seen initially on well-formed, larger vessels within the embryonic lung bud and progressively on finer vascular networks. Each was also expressed on surrounding nonvascular structures. The localization of Notch1 and Jagged1 on endothelial cell surface membranes within the alveolar microvasculature was confirmed by immuno-electron microscopy. These temporal and spatial patterns in Notch1/Jagged1 gene and protein expression suggest multiple potential paths of cell-cell signaling during lung development and vascular morphogenesis.

Chronic Hypoxia and Rat Lung Development: Analysis by Morphometry and Directed Microarray

“…The Notch signaling pathway plays an important role in the regulation of arterialvenous differentiation. Jagged 2 is expressed in endothelial cells in developing lungs (18,19). The Notch ligand negatively regulated vascularization during development and interruption of Notch signaling increases number of lung buds and branching morphogenesis, although the exact role of Jagged 2 in the developing lungs has not been clearly defined (20 -22).…”

Early temporal‐specific responses and differential sensitivity to lithium and Wnt‐3A exposure during heart development

“…Notch-1 is a known early factor important in cell fate decisions, boundary development, epithelial to mesenchymal transition (EMT) cell shape changes, and has been implicated with heart valve development at later stages (Artavanis-Tsakonis et al, 1983;Conlon et al, 1995;Micchelli and Blair, 1999;McLaughlin et al, 2000;Rones et al, 2000;Taichman et al, 2002;Kikuchi et al, 2004;Timmerman et al, 2004). EMT transition or the converse, mesenchymal to epithelial transformation, is an important step in cardiac organogenesis (Linask, 1992a,b).…”

Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice

“…However, as the lung matures, Notch3 expression is restricted to the smooth muscle layer of arterial blood vessels (Villa et al, 2001). Notch1 and Jagged1 transcripts can be detected in the developing epithelium of the airways as early as E11, whereas the expression of Delta1, another ligand for Notch1, is detected in foci of the developing bronchi when examined on E15.5 (Beckers et al, 1999;Taichman et al, 2002). Mammalian homolog of achaete-scute complex (Mash1), a component of the Notch signaling pathway, is required for the normal differentiation of the pulmonary neuroendocrine cells, and its constitutive expression promotes airway dysplasia and neuroendocrine tumors (Ito et al, 2000;Linnoila et al, 2000).…”