Jagged1 is the major regulator of notch‐dependent cell fate in proximal airways

ABSTRACT Background: The Notch signaling pathway plays complex roles in developing lungs, including regulation of proximodistal fates, airway cell specification and differentiation. However, the specific Notch‐mediated signals involved in lung development remain unclear. Results: Here we report that...

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Veröffentlicht in:Developmental dynamics 2013-06, Vol.242 (6), p.678-686
Hauptverfasser: Zhang, Shubing, Loch, Amanda J., Radtke, Freddy, Egan, Sean E., Xu, Keli
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container_end_page 686
container_issue 6
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container_title Developmental dynamics
container_volume 242
creator Zhang, Shubing
Loch, Amanda J.
Radtke, Freddy
Egan, Sean E.
Xu, Keli
description ABSTRACT Background: The Notch signaling pathway plays complex roles in developing lungs, including regulation of proximodistal fates, airway cell specification and differentiation. However, the specific Notch‐mediated signals involved in lung development remain unclear. Results: Here we report that Jagged1 is expressed in a subset of bronchial and bronchiolar epithelial cells, where it controls proximal airway cell fate and differentiation. In agreement with previous studies involving disruption of all Notch signaling, we found that deletion of Jagged1 in airway epithelium increased the number of ciliated cells at the expense of Clara cells, a phenotype associated with downregulation of Hes1. Deletion of Jagged1 also led to an increased number of pulmonary neuroendocrine cells (PNEC), suggesting that Jagged1/Notch signaling inhibits PNEC cell fate. As expected, Jagged1 deletion did not affect alveolar cell differentiation, although alveolar septation was impaired, likely an indirect effect of proximal airway defects. Finally, in the postnatal lung, Jagged1 deletion induced mucous metaplasia, accompanied by downregulation of Hes1 and Hes5. Conclusions: Our results demonstrate that Jagged1‐mediated Notch signaling regulates multiple cell fate decisions as well as differentiation in the respiratory system to coordinate lung development and to maintain a balance of airway cell types in adult life. Developmental Dynamics 242:678–686, 2013. © 2013 Wiley Periodicals, Inc. Key Findings Jagged1 regulates airway cell fate decision in the developing lung Jagged1 prevents mucous metaplasia in the postnatal lung Jagged1 influences alveologenesis
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However, the specific Notch‐mediated signals involved in lung development remain unclear. Results: Here we report that Jagged1 is expressed in a subset of bronchial and bronchiolar epithelial cells, where it controls proximal airway cell fate and differentiation. In agreement with previous studies involving disruption of all Notch signaling, we found that deletion of Jagged1 in airway epithelium increased the number of ciliated cells at the expense of Clara cells, a phenotype associated with downregulation of Hes1. Deletion of Jagged1 also led to an increased number of pulmonary neuroendocrine cells (PNEC), suggesting that Jagged1/Notch signaling inhibits PNEC cell fate. As expected, Jagged1 deletion did not affect alveolar cell differentiation, although alveolar septation was impaired, likely an indirect effect of proximal airway defects. Finally, in the postnatal lung, Jagged1 deletion induced mucous metaplasia, accompanied by downregulation of Hes1 and Hes5. Conclusions: Our results demonstrate that Jagged1‐mediated Notch signaling regulates multiple cell fate decisions as well as differentiation in the respiratory system to coordinate lung development and to maintain a balance of airway cell types in adult life. Developmental Dynamics 242:678–686, 2013. © 2013 Wiley Periodicals, Inc. 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Conclusions: Our results demonstrate that Jagged1‐mediated Notch signaling regulates multiple cell fate decisions as well as differentiation in the respiratory system to coordinate lung development and to maintain a balance of airway cell types in adult life. Developmental Dynamics 242:678–686, 2013. © 2013 Wiley Periodicals, Inc. 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subjects airway cell fate
Animals
Calcium-Binding Proteins - genetics
Calcium-Binding Proteins - physiology
Cell Differentiation
Cell Lineage
Epithelial Cells - metabolism
Gene Expression Regulation, Developmental
Immunohistochemistry
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - physiology
Jagged-1 Protein
Jagged1
lung
Lung - embryology
Lung - metabolism
Membrane Proteins - genetics
Membrane Proteins - physiology
Mice
Mice, Transgenic
mucous metaplasia
Neuroendocrine Cells - metabolism
Notch
Phenotype
Receptors, Notch - metabolism
Serrate-Jagged Proteins
Signal Transduction
Time Factors
title Jagged1 is the major regulator of notch‐dependent cell fate in proximal airways
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