Wnt3A regulates Lef-1 expression during airway submucosal gland morphogenesis
Submucosal glands (SMGs) are epithelial derived branching structures that reside beneath the nasal and proximal conducting airway epithelium. In the human airway, aberrant SMG function is thought to play an important role in airway hypersecretory diseases such as asthma, chronic bronchitis, and cyst...
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| Format: | Dissertation |
| Language: | English |
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ProQuest Dissertations & Theses
01-01-2006
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| Online Access: | Get full text |
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| Summary: | Submucosal glands (SMGs) are epithelial derived branching structures that reside beneath the nasal and proximal conducting airway epithelium. In the human airway, aberrant SMG function is thought to play an important role in airway hypersecretory diseases such as asthma, chronic bronchitis, and cystic fibrosis (CF). SMG hypertrophy and hyperplasia are thought to aggravate the pathoprogression of these diseases through excessive production of airway mucus. Hence, a better understanding of the regulatory pathways controlling the morphogenesis and growth of SMGs may aid the development of therapies for these diseases. However, the mechanisms for SMG development are poorly understood. It has been discovered that the HMG transcription factor, Lef-1, is essential for SMG morphogenesis, as Lef-1 knockout (KO) mice have been shown to lack these structures. In an effort to better understand the regulatory mechanisms that control Lef-1 during airway SMG development, I have studied its transcriptional regulation. I have discovered that a Wnt Responsive Element (WRE) in the Lef-1 promoter is necessary for reporter gene expression during airway SMG morphogenesis using transgenic mice harboring a human Lef-1 promoter fragment controlling LacZ expression. The WRE has previously been shown to be necessary for Wnt3a induction of the promoter in cell culture studies. Consequently, my central hypothesis is that Wnt3a regulates Lef-1 expression through β-catenin/Tcf action at the Lef-1 promoter during SMG morphogenesis. I demonstrate activation of beta-catenin/Tcf complexes during early phases of SMG development and discovered that Tcf4 is the only Tcf factor expressed in the developing airway SMGs prior to the induction of Lef-1. Chromatin Immunoprecipitations (ChIPs) revealed that Tcf4 also associated with the WIRE in the Lef-1 promoter. Using Wnt3a KO mice I show that Wnt3a is necessary for the induction of Lef-1 expression in the nasal SMG buds. Lef-1 KO nasal SMG morphogenesis revealed that they also had placode formation, but lacked normal SMG maturation. My findings provide the first in vivo evidence that Wnt3a can regulate Lef-1 expression at the transcriptional level, while revealing that SMG placode formation does not require Wnt3a induction of Lef-1 expression but requires Lef-1 expression for maturation of the developing SMG. |
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| ISBN: | 1109864221 9781109864229 |