Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways

Arjun Guha, Michelle Vasconcelos, Yan Cai, Mitsuhiro Yoneda, Anne Hinds, Jun Qian, Guihua Li, Lauren Dickel, Jane E. Johnson, Shioko Kimura, Jinjin Guo, Jill McMahon, Andrew P. McMahon, Wellington V. Cardoso

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Abstract

Clara cells of mammalian airways have multiple functions and are morphologically heterogeneous. Although Notch signaling is essential for the development of these cells, it is unclear how Notch influences Clara cell specification and if diversity is established among Clara cell precursors. Here we identify expression of the secretoglobin Scgb3a2 and Notch activation as early events in a program of secretory cell fate determination in developing murine airways. We show that Scgb3a2 expression in vivo is Notch-dependent at early stages and ectopically induced by constitutive Notch1 activation, and also that in vitro Notch signaling together with the pan-airway transcription factor Ttf1 (Nkx2.1) synergistically regulate secretoglobin gene transcription. Furthermore, we identified a subpopulation of secretory precursors juxtaposed to presumptive neuroepithelial bodies (NEBs), distinguished by their strong Scgb3a2 and uroplakin 3a (Upk3a) signals and reduced Ccsp (Scgb1a1) expression. Genetic ablation of Ascl1 prevented NEB formation and selectively interfered with the formation of this subpopulation of cells. Lineage labeling of Upk3a-expressing cells during development showed that these cells remain largely uncommitted during embryonic development and contribute to Clara and ciliated cells in the adult lung. Together, our findings suggest a role for Notch in the induction of a Clara cell-specific program of gene expression, and reveals that the NEB microenvironment in the developing airways is a niche for a distinct subset of Clara-like precursors.

Original languageEnglish (US)
Pages (from-to)12592-12597
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number31
DOIs
StatePublished - Jul 31 2012

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Neuroepithelial Bodies
Secretoglobins
Uroplakins
Embryonic Development

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Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways. / Guha, Arjun; Vasconcelos, Michelle; Cai, Yan; Yoneda, Mitsuhiro; Hinds, Anne; Qian, Jun; Li, Guihua; Dickel, Lauren; Johnson, Jane E.; Kimura, Shioko; Guo, Jinjin; McMahon, Jill; McMahon, Andrew P.; Cardoso, Wellington V.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 31, 31.07.2012, p. 12592-12597.

Research output: Contribution to journalArticle

Guha, A, Vasconcelos, M, Cai, Y, Yoneda, M, Hinds, A, Qian, J, Li, G, Dickel, L, Johnson, JE, Kimura, S, Guo, J, McMahon, J, McMahon, AP & Cardoso, WV 2012, 'Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 31, pp. 12592-12597. https://doi.org/10.1073/pnas.1204710109
Guha, Arjun ; Vasconcelos, Michelle ; Cai, Yan ; Yoneda, Mitsuhiro ; Hinds, Anne ; Qian, Jun ; Li, Guihua ; Dickel, Lauren ; Johnson, Jane E. ; Kimura, Shioko ; Guo, Jinjin ; McMahon, Jill ; McMahon, Andrew P. ; Cardoso, Wellington V. / Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 31. pp. 12592-12597.
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AU - Cai, Yan

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AU - Hinds, Anne

AU - Qian, Jun

AU - Li, Guihua

AU - Dickel, Lauren

AU - Johnson, Jane E.

AU - Kimura, Shioko

AU - Guo, Jinjin

AU - McMahon, Jill

AU - McMahon, Andrew P.

AU - Cardoso, Wellington V.

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N2 - Clara cells of mammalian airways have multiple functions and are morphologically heterogeneous. Although Notch signaling is essential for the development of these cells, it is unclear how Notch influences Clara cell specification and if diversity is established among Clara cell precursors. Here we identify expression of the secretoglobin Scgb3a2 and Notch activation as early events in a program of secretory cell fate determination in developing murine airways. We show that Scgb3a2 expression in vivo is Notch-dependent at early stages and ectopically induced by constitutive Notch1 activation, and also that in vitro Notch signaling together with the pan-airway transcription factor Ttf1 (Nkx2.1) synergistically regulate secretoglobin gene transcription. Furthermore, we identified a subpopulation of secretory precursors juxtaposed to presumptive neuroepithelial bodies (NEBs), distinguished by their strong Scgb3a2 and uroplakin 3a (Upk3a) signals and reduced Ccsp (Scgb1a1) expression. Genetic ablation of Ascl1 prevented NEB formation and selectively interfered with the formation of this subpopulation of cells. Lineage labeling of Upk3a-expressing cells during development showed that these cells remain largely uncommitted during embryonic development and contribute to Clara and ciliated cells in the adult lung. Together, our findings suggest a role for Notch in the induction of a Clara cell-specific program of gene expression, and reveals that the NEB microenvironment in the developing airways is a niche for a distinct subset of Clara-like precursors.

AB - Clara cells of mammalian airways have multiple functions and are morphologically heterogeneous. Although Notch signaling is essential for the development of these cells, it is unclear how Notch influences Clara cell specification and if diversity is established among Clara cell precursors. Here we identify expression of the secretoglobin Scgb3a2 and Notch activation as early events in a program of secretory cell fate determination in developing murine airways. We show that Scgb3a2 expression in vivo is Notch-dependent at early stages and ectopically induced by constitutive Notch1 activation, and also that in vitro Notch signaling together with the pan-airway transcription factor Ttf1 (Nkx2.1) synergistically regulate secretoglobin gene transcription. Furthermore, we identified a subpopulation of secretory precursors juxtaposed to presumptive neuroepithelial bodies (NEBs), distinguished by their strong Scgb3a2 and uroplakin 3a (Upk3a) signals and reduced Ccsp (Scgb1a1) expression. Genetic ablation of Ascl1 prevented NEB formation and selectively interfered with the formation of this subpopulation of cells. Lineage labeling of Upk3a-expressing cells during development showed that these cells remain largely uncommitted during embryonic development and contribute to Clara and ciliated cells in the adult lung. Together, our findings suggest a role for Notch in the induction of a Clara cell-specific program of gene expression, and reveals that the NEB microenvironment in the developing airways is a niche for a distinct subset of Clara-like precursors.

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