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Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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Notch Signaling in Embryology and Cancer edited by Jörg Reichrath and Sandra Reichrath.
©2010 Landes Bioscience and Springer Science+Business Media.
Read this chapter in the Madame Curie Bioscience Database here.

Notch signaling plays an essential role in development and homeostasis of multiple organs including the lung. Dysregulation of Notch signaling has been implicated in various lung diseases including lung cancer. Here we review functions of Notch signaling in coordinating events during lung development, such as early proximodistal fate generation and branching, airway epithelial cell fate specification, alveogenesis and pulmonary vascular development. We also discuss roles of Notch in chronic obstructive pulmonary disease, progressive pulmonary fibrosis, pulmonary arterial hypertension, asthma and lung cancer.


The Notch signaling pathway is ideally suited to precisely regulate cell-cell communication during development of complex tissues like the lung, where multiple cell types must control each other's survival, proliferation, differentiation and patterning. It has long been known that the lung is amongst the richest source of Notch ligand and receptor mRNA. As more information has come to light about how Notch activation is regulated in vivo, it has become increasingly clear that this system is very tightly controlled through cell autonomous and cell non-autonomous mechanisms. For example, the Delta/Dll-family ligands can be cell non-autonomous agonists that efficiently activate Notch on the surface of neighboring cells,1 especially if Notch has been modified by a Fringe glycosyl transferase.2 Serrate/Jagged family ligands function as antagonists capable of inhibiting the Delta-mediated activation of Notch in this context.3 In contrast, Serrate/Jagged ligands function as Notch agonists in cells that do not express Fringe proteins.2-4 Finally, Delta/Dll and Serrate/Jagged ligands function cell autonomously to inhibit Notch receptor activation.1 Thus, activation of a specific Notch receptor in a specific lung cell will depend on whether the cell in question expresses one or other Fringe protein, whether it expresses one or other Notch ligand (to block Notch activation) and to what extent neighboring cells express agonistic ligands in excess of antagonistic ligands.2 This complexity allows for precise coordination of lung cell type specification as outlined below. Unfortunately, the importance of tight regulation of Notch receptor activation in various lung cell types is illustrated by the many pathological states in the lung associated with inappropriate Notch signaling.


The lung is a highly branched organ that develops from definitive endoderm of the embryonic gut (beginning at approximately four weeks in humans and embryonic day 9.5 (E9.5) in mice). Epithelial differentiation varies along the proximodistal axis, with the surface epithelium of proximal airways (trachea and bronchi) consisting of basal cells, ciliated cells, goblet cells and neuroendocrine cells. Also found in the proximal region are submucosal glands, which consist of a mixture of mucous and serous cells. Distal to the trachea and bronchi is an extensive network of bronchioles which are lined with ciliated cells and Clara cells and rare populations of neuroendocrine cells. Alveoli are the most distal part of the lungs and are lined with flattened type I pneumocytes and cuboidal surfactant-producing type II pneumocytes. While airway epithelia of humans and rodents are similar, there are differences. Notably, in proximal airways of mice there are fewer basal cells, goblet cells and submucosal glands, but a large number of Clara cells. In humans, Clara cells are found only in bronchioles.

Notch signaling pathway genes are expressed in the developing lung as early as bud formation. Within budding epithelium, expression of Notch1, Jagged1 and Jagged2 are restricted to the distal area, while Dll1 expression is found in the proximal region.5,6 These expression patterns raise the possibility that Notch signaling may control cell fate specification along the proximodistal axis. In experiments on E8.5 murine lung explants, inhibition of Notch signaling with γ-secretase inhibitor (DAPT) causes expansion of Nkx2.1-expressing distal tip progenitors.5 Older, DAPT-treated, explants (E11.5) display ectopic buds in proximal regions and an increase in the number and size of distal buds. These effects are likely caused by inhibiting Notch1, as antisense oligonucleotides targeting this gene cause increased branching in cultured embryonic lung buds, while antisense oligonucleotides against other Notch receptors do not.6 Concomitant with an increase in distally-fated cells, DAPT-treated explants show a reduction in SOX2-expressing proximally-fated cells.5 SOX2 is necessary for the generation and/or maintenance of several proximal cell lineages such as basal and Clara cells.7,8 A requirement for Notch signaling in promoting a SOX2 proximal fate is also supported by the finding that conditional deletion of Pofut1, which codes for an O-fucosyltransferase essential for Notch protein function, strongly reduces SOX2 expression in E18.5 embryos.9 Activation of Notch signaling at this stage may be driven by FGF10, a regulator of early lung morphogenesis. In E11.5 lung explants, engraftment of an FGF10 bead caused increased Notch1, Jagged1 and Jagged2 expression.5 Thus, FGF10 may simultaneously promote early proximal and distal cell fates, with the former being driven by induction of Notch1 signaling. Two complications to this model, however, are the findings that conditional deletion of Pofut1 or Rbpjk, the major transcriptional effector of canonical Notch signaling, does not result in overt alveolar defects.9 Thus, while Notch signaling promotes early proximal fates marked by SOX2 expression, the physiologic role for Notch in regulating distal progenitor cell identity is less clear.

In addition to regulating early proximodistal cell fate, Notch signaling also regulates later cytodifferentiation of specific lineages. These are generated by distinct stem/progenitor cells found within different segments of the airway. In the trachea and mainstem bronchi, p63+ and cytokeratin 5/14+ basal cells self-renew and generate Clara (in the mouse) and ciliated cell lineages.10,11 In bronchioles, CCSP+ Clara cells self-renew and generate ciliated cells.12 Deletion of one of the Notch target genes, Hes1, results in a mild reduction of Clara cells in bronchial and bronchiolar epithelia, while disruption of Notch signaling through conditional deletion of Pofut1 or Rbpjk results in a dramatic loss of Clara cells and increased ciliated cell number.9,13 Despite a reduction in SOX2+ cells in these mutant animals, basal and goblet cell numbers are normal at E18.5. These data suggest that while SOX2 expression, promoted by Notch, may not be necessary to generate basal cells, it may be necessary to promote Clara cell generation and/or maintenance. However, ablation of SOX2 in Clara cells results in a loss of Clara cells and their ciliated progeny,7 while deletion of Pofut1 or Rbpjk results in a loss of Clara cells and an increase in ciliated cell number.9 It is, therefore, likely that the effect of Notch on Clara cells is independent of SOX2. Furthermore, since the Clara cell lineage is affected in bronchioles, where there are no basal cells, it is also likely that Notch signaling acts within Clara cells to promote their identity rather than on basal cells to promote Clara cell fate. Consistent with this model, Notch reporter activity, as well as the Notch1 intracellular domain (N1ICD) are detected in Clara cells and conditional deletion of Rbpjk in CCSP+ cells depletes the Clara cell compartment.14 In an elegant set of experiments, it was shown that, following injury, Clara cells are generated from a population of cells that initially do not receive a Notch signal, but eventually turn it on prior to expression of CCSP.14 Thus, Notch signaling may not be necessary for maintenance of Clara cell precursors, but for their differentiation. Further support for this comes from the observation that transgenic misexpression of N1ICD in distal epithelial cells via the SPC promoter results in ectopic expression of the Clara cell marker CCSP.15 "Salt and pepper" staining of Jagged1 in ciliated cells and N1ICD in Clara cells suggest that lateral signaling from ciliated cells promotes Clara cell identity. Indeed, in the absence of such signaling, cells normally fated to become Clara cells differentiate through a default program into ciliated cells.9,14

Another lineage regulated by Notch signaling is the pulmonary neuroendocrine cell (PNEC). Evidence for the role of Notch in regulating PNEC differentiation first came from an elegant study by Ito et al.13 The Notch target gene Hes1 is expressed in nonneuroendocrine cells, whereas Ash1, a neurogenic basic helix-loop-helix transcription factor, is expressed in neuroendocrine cells. Hes1 deficient mice show increased numbers of Ash1+ PNECs, while Ash1 deficient mice lack PNECs.13,16 This mutually exclusive relationship results from direct repression of the Ash1 promoter by Hes1 and a Hes1-independent ability of Notch1 to promote Ash1 degradation.17,18 Notch1 may, therefore, drive Hes1 expression and inhibition of PNEC fate, since Notch1 antisense oligonucleotides promote PNEC differentiation and transgenic expression of N1ICD under control of a neuroendocrine specific promoter inhibits PNEC differentiation.6,19 This model is further supported by the fact that Dll1 is expressed in neuroendocrine cells, whereas Notch1,2 and 3 are expressed in nonneuroendocrine cells.20,21 Thus, Dll1-mediated Notch activation could well induce Hes1 expression and suppress neuroendocrine differentiation through lateral inhibition. An important caveat to this model, however, is the recent finding that conditional deletion of Rbpjk in lung endoderm does not strongly affect Hes1 expression or the number of PNECs.14 Thus, it's possible that under physiologic conditions, a noncanonical pathway might drive Hes1 expression and inhibition of PNEC fate. Such a mechanism could well employ alternative upstream signaling from FGFR, JAK, or ERK kinases.22,23

Pulmonary goblet cell fate is also regulated by Notch. However, the physiologic role for Notch in this context has been difficult to precisely define due to the low number of these cells in murine airway epithelium. In murine tracheal explant studies and in human airway cell cultures, Dll4 increases the number of MUC5AC+ goblet cells.15 Similarly, expression of N1ICD under control of the SPC promoter increases goblet cell numbers in proximal airways.15 Conversely, gamma secretase inhibitor treatments block IL-13-induced Muc5AC expression in human airway cell cultures.15 Thus, high levels of Notch ICD appear to drive goblet cell identity in proximal airways and may also be necessary for IL-13-mediated goblet cell differentiation. However, once again, conditional deletion of Rbpjk in the lung endoderm does not affect the number of goblet cells, making it difficult to conclusively establish the physiologic role for Notch signaling in goblet cell differentiation.9 Studies in the gut suggest that Notch regulation of goblet cell differentiation can be complex, with Notch signaling performing opposite roles towards goblet cell fate in mitotic stem cells and postmitotic differentiated cells.24-26


Alveolar development in the distal lung occurs through coordinated events in three cellular compartments: epithelium, endothelium and mesenchymal stroma. Notch signaling is known to play important roles in cell fate specification and cell differentiation in the parenchyma and vascular compartments. It is therefore not surprising that Notch may regulate alveolar development by coordinating alveolar epithelial differentiation and capillary formation. As noted above, it is not clear whether Notch signaling plays a direct role in regulating distal progenitor cell fate. Ectopic expression of the Notch3 intracellular domain (N3ICD) in distal lung epithelium causes arrest of alveolar epithelial differentiation, with stalled maturation of type II pneumocytes and no type I pneumocyte development observed.27 Similarly, when constitutively activated N1ICD is expressed in distal lung epithelium, alveolar development is completely abolished.15 Indeed, distal cysts form and cells within these structures do not express alveolar markers.15 These data are consistent with explant studies in which E11.5 explants incubated with DAPT show increased branching as well as greater numbers of Nkx2.1 and SPC+ cells.5 Complicating interpretation of these results, however, are the observations that conditional deletion of Pofut1 or Rbpjk in lung epithelium does not adversely affect distal lung development, including formation of alveolar saccules and differentiation of alveolar epithelial cells.9,14 Similarly, deletion of Lunatic Fringe (Lfng), an N-acetylglucosaminetransferase that modifies Notch receptors to promote Dll ligand-binding and activation causes only mild defects in alveolar epithelium, namely delayed differentiation of type I pneumocytes.21 While Lfng knockout mice do show defective alveolar development with failed alveolar septation, these phenotypes likely arise from defective differentiation and mobilization of myofibroblast cells, rather than alveolar epithelial cells.21 Interestingly, universal deletion of Rbpjk from E14.5 to E18.5 leads to similar defects in myofibroblast differentiation without affecting alveolar epithelial cells.21 In addition, a similar defect is observed in Notch2+/-Notch3-/- compound mutant mice.21 Together with the expression pattern of Notch receptors and ligands in the distal lung during cannalicular and saccular stages, these data support a model whereby Lfng functions to enhance Notch signaling in myofibroblast precursor cells, thereby coordinating differentiation and mobilization of myofibroblasts required for alveolar septation.21

Alveolar development necessarily involves penetration of the growing microvascular network into alveolar walls. This event has to be tightly coordinated with development of alveolar epithelium to ensure lung function at birth. Expression of Notch pathway genes in lung vasculature increases progressively from early to late lung development, suggesting an essential role for Notch signaling in the expanding microvasculature during alveolar development.20,21,28 This idea is consistent with the known role for Notch signaling in vascular development throughout the body.29-34 Many Notch ligand and receptor gene knockouts, including Notch1, Notch2, Jagged1 and Dll1 mutants die relatively early in embryonic development, preventing direct analysis of Notch activation in vascular development of the distal lung. Some evidence for the role of Notch signaling in pulmonary vascular development comes from Foxf1 heterozygous mutants, where Foxf1 haploinsufficiency disrupts pulmonary expression of Notch2 and its downstream target Hes1. This is associated with abnormal morphogenesis of lung microvasculature and neonatal lethality, although the cell type directly affected by Foxf1 haploinsufficiency and reduced Notch2 expression remains unclear.35 Notch3 and Notch4 mutant mice are viable and have at least superficially normal lungs.36-38 However, expression of constitutively activated N4ICD in vascular endothelium results in lung arteriovenous shunts.39 As in other contexts, aberrant Notch activation may inhibit vessel sprouting, leading to vessel enlargement at the capillary bed interface and ultimately to arteriovenous shunts.


Notch signaling regulates development of airway epithelium, mesenchymal stroma and pulmonary vasculature as noted above. Notch also regulates these and other cell types in the adult lung. Minor injuries that require repair occur continuously in mature lungs. Given that Notch activation controls stem cell maintenance and differentiation, cell proliferation and apoptosis, it is not surprising that Notch signaling could be directly involved in the response of lungs to injury. Chronic Obstructive Pulmonary Disease (COPD), often caused by smoking, is associated with down-regulation of Notch pathway genes, including Dll1, Notch3, Hes5, Hey1 and Hey2.40 Thus, it is speculated that reduced Notch signaling in this context may promote differentiation of airway epithelial progenitors during the repair of lung injury. Further studies on the functional significance of Notch pathway downregulation in COPD should provide insight into its role in disease establishment or progression.

Progressive pulmonary fibrosis is a common and ultimately fatal disease of the lung. It is characterized by fibroblast proliferation, extracellular matrix deposition and chronic remodeling of airways. de novo emergence of myofibroblasts plays a key role in pathogenesis of pulmonary fibrosis. TGF-β and other fibrogenic cytokines are known inducers of myofibroblast differentiation. Recently, Notch1 activation has been shown to induce myofibroblast differentiation by directly stimulating α-SMA expression41 and upregulation of Notch1, as well as Jagged1 and Hes1, appears to be downstream of Found in inflammatory zone 1 (FIZZ1) in myofibroblast induction.42 It is interesting to note that Lfng-mediated Notch signaling is also required for physiological myofibroblast differentiation during lung alveogenesis, although different Notch ligands and receptors are likely involved.21

Pulmonary Arterial Hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular overload and eventually to right ventricular failure and death. Histopathological features of PAH include thickened vessel wall and luminal occlusion of the small pulmonary arteries and arterioles due to proliferation of vascular Smooth Muscle Cells (vSMC) and endothelial cells. Notch signaling has been shown to regulate differentiation and homeostasis of vSMC. In the developing lung, RBPJκ-mediated Notch signaling is required for recruitment and specification of arterial vascular smooth muscle cells.14 Recently, Li et al reported that Notch3 signaling promotes pulmonary arterial hypertension.43 Indeed, human pulmonary hypertension is associated with elevated NOTCH3 expression in smooth muscle cells of small pulmonary arteries and disease severity correlated with NOTCH3 protein level. Deletion of Notch3 in mice prevented pulmonary hypertension in response to hypoxic stimulation.43 Furthermore, pulmonary hypertension can be successfully treated in mice by administration of γ-secretase inhibitor that blocks Notch3 signaling. HES-5 was downstream of Notch3 in this context and controlled proliferation as well as pulmonary vSMC phenotypes.43

Notch signaling plays essential roles in development of hematopoietic cells (reviewed in other sections of this book). Many lung disorders, including chronic inflammation and asthma, are mediated by an inappropriate and/or sustained immune response. Notch ligands Dll4 and Jagged1 regulate differentiation and function of T-cells in response to viral or mycobacterial infection in the lung. Dll4 regulates disease pathogenesis during respiratory viral infections by modulating Th2 cytokines to maintain a Th1 environment.44 During a mycobacterial challenge to the lung, dendritic cells induce differentiation of Th17 cells through a TLR9 effector pathway that upregulates Dll4. Decreased expression of Dll4 in this context led to abrogation of the Th17 phenotype in Tlr9-/- mice, with concomitant increase in granuloma size.45 In an allergic airway condition such as asthma, Dll4 and Jagged1 exerted opposite effects. Dll4 was preferentially expressed by regulatory T-cells to suppress neovasculature remodeling of the airway via proapoptotic Dll4-mediated Notch signaling, therefore alleviating airway hyperresponsiveness in chronic asthma.46 In contrast, Jagged1 helped initiate lung allergic responsiveness. Indeed, interactions between Notch receptors on CD4+ T-cells and Jagged1 on APCs can stimulate IL-4 production and Th2 differentiation, leading to airway hyperresponsiveness and allergic airway inflammation.47


Lung cancers are histologically and molecularly diverse. One sub-group, Small Cell Lung Cancer (SCLC), has neuroendocrine-like molecular features, whereas all other types do not and are referred to collectively as non Small Cell Lung Cancer (NSCLC). SCLCs, which express PNEC markers including Ash1, show no evidence of Notch pathway activation. As discussed above, Ash1 null mice do not have PNECs, as assessed using canonical neuroendocrine markers.13,16 Similarly, knockdown of Ash1 in SCLC causes suppression of neuroendocrine marker gene expression, as well as growth arrest and apoptosis.16,48,49 Interestingly, activated N1ICD or N2ICD can both suppress Ash1 expression in SCLC, an effect reminiscent of Notch-induced suppression of Ash1 in development.17,18,50 This effect, not surprisingly, is associated with Notch-induced growth arrest of SCLC cells.46

The first evidence of an oncogenic role for Notch in lung cancer came from studies on a tumor-associated translocation between chromosome 15 and 19. Overexpression of wildtype NOTCH3, which maps to chromosome 19 near the breakpoint, was observed in this tumor.51 Interestingly, this NOTCH3 expressing tumor was poorly differentiated and could not be assigned to a particular histological class of lung cancer. Indeed, expression of N3ICD in distal lung epithelium of SPC-N3ICD transgenic mice, causes a dramatic block in differentiation of alveolar cell types.27 Elevated wildtype NOTCH3 expression has subsequently been observed in 30-40% of primary human lung tumors, typically at a level of expression and/or activity that allows for histological classification.52 Notch3 is frequently co-expressed with EGFR in NSCLC. In lung cancer cell lines co-expressing both receptors, suppression of Notch3 activity sensitizes cells to EGFR inhibitors.52,53 These data suggest the Notch3 and EGFR pathways cooperate to promote tumorigenesis. One potential mechanism for such cooperation may be through suppression of the pro-apoptotic gene, Bim.54 However, another potential mechanism for cooperation could involve EGFR-induced activation of an IL-6 to carbonic anhydrase IX (CA9) pathway, which promotes survival of cells growing under hypoxic conditions. Lung cancers with mutant EGFR show IL-6/Stat3-induced cell growth.55,56 In breast cancer cells, IL-6 is also frequently elevated, which can lead to increased expression of Jagged1, Notch3 and CA9; as well as enhanced invasiveness and survival under hypoxic conditions.57 Since Notch3 induction and signaling are required for the pro-tumorigenic effects of IL-6 in breast cancer cells, it is possible that Notch3 may play a similar role in lung cancer cells.57

In addition to NOTCH3, other Notch family members display elevated expression and/or activity in NSCLC.53 Furthermore, 30% of primary lung cancers show severely reduced or loss of Numb expression. Numb is a conserved inhibitor of Notch signaling and absence of Numb expression inversely correlates with activation of Notch1.58 10% of NSCLC samples show gain-of-function mutations in NOTCH1 that affect heterodimerization or PEST domains, as observed in T-cell ALL. Furthermore, in tumors without p53 mutations, the presence of activated NOTCH1 correlates with poor prognosis.58

Recent analyses of Notch receptor expression and signaling in lung cancer cell lines have been performed under hypoxic conditions, which may better mimic the environment experienced by lung tumor cells in vivo.59-61 In one study it was found that Notch1 signaling is higher under hypoxic conditions and that this signaling is necessary for cancer cell survival.60 In contrast, under normoxic conditions, N1ICD promotes apoptosis.60 Survival is likely mediated, in part, by N1ICD-induced stimulation of IGF1R transcription, which promotes AKT phosphorylation.61 It is also possible that hypoxia-induced expression of HIF1α might cooperate with N1ICD to promote survival, similar to their cooperative interactions in maintaining hypoxic neuronal and myogenic stem/progenitor cells in an undifferentiated state.62 Collectively, these studies highlight the importance and complexity of Notch signaling in lung carcinogenesis, with the cellular (SCLC vs NSCLC) and microenvironmental (hypoxia) context profoundly effecting tumor cell response to Notch activation.


Over the past decade, emerging evidence has established that Notch signaling regulates lung development as well as pathological conditions of the lung. In the developing lung, Notch signaling promotes early proximal cell fates, regulates later cytodifferentiation of airway epithelium into specific lineages (Clara cells versus ciliated cell; neuroendocrine cells versus nonneuroendocrine cells) and coordinates alveolar development. In pathological conditions such as COPD, fibrosis and lung cancer, Notch signaling may exert its impact by regulating stem cell activity, cell differentiation, cell proliferation and apoptosis, reminiscent of its roles during lung development. For instance, COPD is associated with down-regulation of Notch pathway genes, suggesting a role for Notch during repair of injured lungs. Notch pathway exhibits differential properties of tumor promotion or suppression depending on the type of lung tumor. NSCLC show increased Notch signaling and may actively depend on this pathway for tumor cell survival, whereas Notch signaling is not activated in SCLC and may even inhibit growth of these tumors. Notch genes play critical roles in both normal and cancer stem cells of many tissues. They likely function to control survival, self-renewal and differentiation of lung stem cells as well. Future studies to define the expression and function of Notch ligands, receptors and target genes in specific lung lineages as well as in stem and progenitor cells throughout the pulmonary epithelial stem cell hierarchy should help define precisely how Notch signaling regulates lung development and disease.


The authors thank members of the Egan and Moghal labs. K.X. was supported by a CIHR fellowship. S.E.E.'s lab has been supported by funds from the Canadian Cancer Society Research Institute. N. M. is a recipient of an investigator award from the Ontario Institute for Cancer Research.


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