The loss of Hoxa5 function promotes Notch-dependent goblet cell metaplasia in lung airways
Summary Hox genes encode transcription factors controlling complex developmental processes in various organs. Little is known, however, about how HOX proteins control cell fate. Herein, we demonstrate that the goblet cell metaplasia observed in lung airways from Hoxa5−/− mice originates from the tra...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2012-05-01
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| Series: | Biology Open |
| Subjects: | |
| Online Access: | http://bio.biologists.org/content/1/7/677 |
| _version_ | 1818436826580385792 |
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| author | Olivier Boucherat Jamila Chakir Lucie Jeannotte |
| author_facet | Olivier Boucherat Jamila Chakir Lucie Jeannotte |
| author_sort | Olivier Boucherat |
| collection | DOAJ |
| description | Summary
Hox genes encode transcription factors controlling complex developmental processes in various organs. Little is known, however, about how HOX proteins control cell fate. Herein, we demonstrate that the goblet cell metaplasia observed in lung airways from Hoxa5−/− mice originates from the transdifferentiation of Clara cells. Reduced CC10 expression in Hoxa5−/− embryos indicates that altered cell specification occurs prior to birth. The loss of Hoxa5 function does not preclude airway repair after naphthalene exposure, but the regenerated epithelium presents goblet cell metaplasia and less CC10-positive cells, demonstrating the essential role of Hoxa5 for correct differentiation. Goblet cell metaplasia in Hoxa5−/− mice is a FOXA2-independent process. However, it is associated with increased Notch signaling activity. Consistent with these findings, expression levels of activated NOTCH1 and the effector gene HEY2 are enhanced in patients with chronic obstructive pulmonary disease. In vivo administration of a γ-secretase inhibitor attenuates goblet cell metaplasia in Hoxa5−/− mice, highlighting the contribution of Notch signaling to the phenotype and suggesting a potential therapeutic strategy to inhibit goblet cell differentiation and mucus overproduction in airway diseases. In summary, the loss of Hoxa5 function in lung mesenchyme impacts on epithelial cell fate by modulating Notch signaling. |
| first_indexed | 2024-12-14T17:14:57Z |
| format | Article |
| id | doaj.art-19b72f96279d4e04812421f36a36a1f3 |
| institution | Directory Open Access Journal |
| issn | 2046-6390 |
| language | English |
| last_indexed | 2024-12-14T17:14:57Z |
| publishDate | 2012-05-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Biology Open |
| spelling | doaj.art-19b72f96279d4e04812421f36a36a1f32022-12-21T22:53:26ZengThe Company of BiologistsBiology Open2046-63902012-05-011767769110.1242/bio.2012170120121701The loss of Hoxa5 function promotes Notch-dependent goblet cell metaplasia in lung airwaysOlivier Boucherat0Jamila Chakir1Lucie Jeannotte2 Centre de recherche en cancérologie de l'Université Laval, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, 9 rue McMahon, Québec QC G1R 2J6, Canada Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Centre de recherche de L'Hôpital Laval, Québec QC G1V 4G5, Canada Centre de recherche en cancérologie de l'Université Laval, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, 9 rue McMahon, Québec QC G1R 2J6, Canada Summary Hox genes encode transcription factors controlling complex developmental processes in various organs. Little is known, however, about how HOX proteins control cell fate. Herein, we demonstrate that the goblet cell metaplasia observed in lung airways from Hoxa5−/− mice originates from the transdifferentiation of Clara cells. Reduced CC10 expression in Hoxa5−/− embryos indicates that altered cell specification occurs prior to birth. The loss of Hoxa5 function does not preclude airway repair after naphthalene exposure, but the regenerated epithelium presents goblet cell metaplasia and less CC10-positive cells, demonstrating the essential role of Hoxa5 for correct differentiation. Goblet cell metaplasia in Hoxa5−/− mice is a FOXA2-independent process. However, it is associated with increased Notch signaling activity. Consistent with these findings, expression levels of activated NOTCH1 and the effector gene HEY2 are enhanced in patients with chronic obstructive pulmonary disease. In vivo administration of a γ-secretase inhibitor attenuates goblet cell metaplasia in Hoxa5−/− mice, highlighting the contribution of Notch signaling to the phenotype and suggesting a potential therapeutic strategy to inhibit goblet cell differentiation and mucus overproduction in airway diseases. In summary, the loss of Hoxa5 function in lung mesenchyme impacts on epithelial cell fate by modulating Notch signaling.http://bio.biologists.org/content/1/7/677Hox genesGoblet cellsNotch pathway |
| spellingShingle | Olivier Boucherat Jamila Chakir Lucie Jeannotte The loss of Hoxa5 function promotes Notch-dependent goblet cell metaplasia in lung airways Biology Open Hox genes Goblet cells Notch pathway |
| title | The loss of Hoxa5 function promotes Notch-dependent goblet cell metaplasia in lung airways |
| title_full | The loss of Hoxa5 function promotes Notch-dependent goblet cell metaplasia in lung airways |
| title_fullStr | The loss of Hoxa5 function promotes Notch-dependent goblet cell metaplasia in lung airways |
| title_full_unstemmed | The loss of Hoxa5 function promotes Notch-dependent goblet cell metaplasia in lung airways |
| title_short | The loss of Hoxa5 function promotes Notch-dependent goblet cell metaplasia in lung airways |
| title_sort | loss of hoxa5 function promotes notch dependent goblet cell metaplasia in lung airways |
| topic | Hox genes Goblet cells Notch pathway |
| url | http://bio.biologists.org/content/1/7/677 |
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