Lung morphogenesis is orchestrated through Grainyhead-like 2 (Grhl2) transcriptional programs

The highly conserved transcription factor Grainyhead-like 2 (Grhl2) exhibits a dynamic expression pattern in lung epithelium throughout embryonic development. Using a conditional gene targeting approach to delete Grhl2 in the developing lung epithelium, our results demonstrate that Grhl2 plays multi...

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Bibliographic Details
Published in:Developmental biology 2018-11, Vol.443 (1), p.1-9
Main Authors: Kersbergen, Ariena, Best, Sarah A., Dworkin, Sebastian, Ah-Cann, Casey, de Vries, Michael E., Asselin-Labat, Marie-Liesse, Ritchie, Matthew E., Jane, Stephen M., Sutherland, Kate D.
Format: Article
Language:English
Subjects:
Alveolar Epithelial Cells - metabolism
Alveolar Epithelial Cells - physiology
Animals
Cell Differentiation
DNA-Binding Proteins - metabolism
Down-Regulation
Elf5
Epithelium - metabolism
Gene Expression Profiling
Grhl2
Lung - embryology
Lung - metabolism
Lung - physiology
Lung morphogenesis
Mice - embryology
Progenitor cells
Respiratory Function Tests - methods
Saccule and Utricle - metabolism
SOX9 Transcription Factor
Transcription Factors - metabolism
Transcription Factors - physiology
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Summary:The highly conserved transcription factor Grainyhead-like 2 (Grhl2) exhibits a dynamic expression pattern in lung epithelium throughout embryonic development. Using a conditional gene targeting approach to delete Grhl2 in the developing lung epithelium, our results demonstrate that Grhl2 plays multiple roles in lung morphogenesis that are essential for respiratory function. Loss of Grhl2 leads to impaired ciliated cell differentiation and perturbed formation of terminal saccules. Critically, a substantial increase in Sox9-positive distal tip progenitor cells was observed following loss of Grhl2, suggesting that Grhl2 plays an important role in branching morphogenesis. Gene transcription profiling of Grhl2-deficient lung epithelial cells revealed a significant down regulation of Elf5, a member of the Ets family of transcription factors. Furthermore, ChIP and comparative genomic analyzes confirmed that Elf5 is a direct transcriptional target of Grhl2. Taken together, these results support the hypothesis that Grhl2 controls normal lung morphogenesis by tightly regulating the activity of distal tip progenitor cells. •Grhl2 is a critical transcriptional regulator of respiratory function.•Loss of Grhl2 results in an increase in Sox9-positive distal tip progenitor cells.•Elf5, a transcription factor enriched in lung epithelial tip progenitor cells is downregulated in Grhl2-deficient lungs.•Genomic studies confirmed Elf5 as a novel direct target of Grhl2 in lung epithelium.
ISSN:0012-1606
1095-564X
DOI:10.1016/j.ydbio.2018.09.002