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

Developmental biology

Ariena Kersbergen^1¹  Sarah A. Best^1,2²  Casey Ah-Cann^1,2³  Sebastian Dworkin^3⁴  Michael E. de Vries^3,4⁵  Marie-Liesse Asselin-Labat^1,2⁶ 

[1] ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia^1;Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia^2;Department of Medicine, Monash University Central Clinical School, Prahran, Victoria 3004, Australia^4;Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria 3086, Australia^3;Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia^5;School of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3010, Australia^6

关键词: Grhl2;    Lung morphogenesis;    Progenitor cells;    Elf5;   

DOI  :  10.1016/j.ydbio.2018.09.002

学科分类：生物科学（综合）

来源: Academic Press

【 摘 要 】

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.

【 授权许可】

CC BY