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1 Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, IA, USA
2 Department of Internal Medicine, Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases, University of Iowa College of Medicine, Iowa City, IA, USA
3 Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, IA, USA; Department of Internal Medicine, Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases, University of Iowa College of Medicine, Iowa City, IA, USA
* To whom correspondence should be addressed. E-mail: john-engelhardt{at}uiowa.edu.
Regulated expression of lymphoid enhancer factor 1 (Lef-1) plays an important role in the transcriptional control of epithelial bud formation during organogenesis of many tissues. Although Lef-1 is not required for normal lung development in the mouse, its expression is essential for submucosal gland development in the nasal mucosa and trachea. Mammary glands similarly share a dependence on Lef-1 for normal development. Inductive expression of Lef-1 mRNA is tightly regulated in both epithelial and
mesenchymal cells during development of several bud forming organs, suggesting the involvement of a highly regulated promoter. However, regions of the Lef-1 promoter required for spatial and temporal regulation during glandular development have yet to be defined. We hypothesized that a previously reported 110 bp Wnt-responsive element (WRE) in the Lef-1 promoter, which can be induced by Wnt-
3a/
-Catenin signals, may also play a role in regulating Lef-1 expression during airway and mammary
gland development. Here we show that the Lef-1 promoter is also responsive to Wnt-1 signals in both airway and mammary epithelial cell lines. To better understand the importance of the WRE in dynamically regulating Lef-1 promoter activation in these two types of epithelia in vivo, we utilized LacZ-reporter transgenic mice to evaluate the significance of Wnt-responsive sequences in the Lef-1
promoter during glandular bud formation. A 2.5 kb Lef-1 promoter fragment partially reproduced endogenous Lef-1 expression patterns in a subset of cell types involved in both mammary gland and submucosal gland bud development. Interestingly, removal of the 110 bp WRE from the Lef-1 promoter ablated expression in nasal and tracheal submucosal gland buds while having no significant effect on
developmental expression in mammary gland buds. These findings suggest that Wnt regulation of the Lef-1 promoter at the WRE may play an important role during airway submucosal gland bud formation.
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