Notch Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling

Abstract

Lung development is mediated by assorted signaling proteins and orchestrated by complex mesenchymal-epithelial interactions. Notch signaling is an evolutionarily conserved cell-cell communication mechanism that exhibits a pivotal role in lung development. Notably, both aberrant expression and loss of regulation of Notch signaling are critically linked to the pathogenesis of various lung diseases, in particular, pulmonary fibrosis, lung cancer, pulmonary arterial hypertension, and asthmatic airway remodeling; implying that precise regulation of intensity and duration of Notch signaling is imperative for appropriate lung development. Moreover, evidence suggests that Notch signaling links embryonic lung development and asthmatic airway remodeling. Herein, we summarized all-recent advances associated with the mechanistic role of Notch signaling in lung development, consequences of aberrant expression or deletion of Notch signaling in linking early-impaired lung development and asthmatic airway remodeling, and all recently investigated potential therapeutic strategies to treat asthmatic airway remodeling.

Expression of Notch receptors and their ligands in pancreatic ductal adenocarcinoma

“…The Notch gene was first identified in Drosophila in 1917 ( 19 ) and Notch1 was revealed to be associated with T-cell acute lymphoblastic leukemia in 1991 ( 20 ). The roles of the Notch signaling pathway in embryonic development ( 21 , 22 ), adult differentiation ( 23 , 24 ), and the development tumors ( 10 – 13 ) have been previously studied and positively confirmed. In eukaryotes, the Notch signaling pathway is highly conserved and regulates cell proliferation, differentiation and apoptosis through interactions between adjacent cells ( 25 – 27 ).…”

Eosinophil accumulation in postnatal lung is specific to the primary septation phase of development

“…While mesenchymal activity and developmental pathways (WNT, Smoothened/Disheveled, Notch) are getting more attention in asthma and allergy research [37][38][39][40][41] , the functional contribution of the ECM to allergic disease pathogenesis and eosinophil biology is surprisingly overlooked. The ECM is not a passive structure but plays numerous critical regulatory roles in dictating the progression of morphogenetic events, recruitment and activation of hematopoietic and structural cells, and control of differentiation and fate of different cell types.…”

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

“…Notch is another developmental control pathway that regulates cell differentiation and fate through mechanisms involving lateral inhibition [153]. Upon ligand binding, Notch receptors (Notch 1 through 4) are cleaved by γ-secretase, which releases the Notch intracellular domain (NICD) that translocates to the nucleus and induces target gene (e.g., HES, HEY) transcription [154].…”