Document Detail

Roles for β-catenin and doxycycline in the regulation of respiratory epithelial cell frequency and function.
MedLine Citation:
PMID:  21852686     Owner:  NLM     Status:  MEDLINE    
The expression of β-catenin-dependent genes can be increased through the Cre recombinase (Cre)-mediated elimination of the exon 3-encoded sequence. This mutant β-catenin is termed DE3, and promotes the expression of β-catenin-dependent genes. Our previous study used the DE3 model to demonstrate that persistent β-catenin activity inhibited bronchiolar Clara-to-ciliated cell differentiation. The present study was designed to evaluate the roles of β-catenin in regulating the tracheal progenitor cell hierarchy. However, initial experiments demonstrated that the tetracycline-responsive element-Cre transgene (TRE-Cre) was active in the absence of a reverse tetracycline transactivator driver or inducer, doxycycline (Dox). This spurious TRE-Cre transgene activity was not detected using the ROSA26-floxed STOP-LacZ reporter. To determine if the phenotype was a consequence of genotype or treatment with Dox, tracheal and lung specimens were evaluated using quantitative histomorphometric techniques. Analyses of uninduced mice demonstrated a significant effect of genotype on tracheal epithelial cell mass, involving basal, Clara-like cell types. The bronchial and bronchiolar Clara cell mass was also decreased. Paradoxically, an effect on ciliated cell mass was not detected. Activation of the β-catenin reporter transgene TOPGal demonstrated that β-catenin-dependent gene expression led to the genotype-dependent tracheal and bronchiolar phenotype. Comparative analyses of wild-type or keratin 14-rtTA(+/0)/TRE-cre(+/0)/DE3(+/+) mice receiving standard or Dox chow demonstrated an effect of treatment with Dox on basal, Clara-like, and Clara cell masses. We discuss these results in terms of cautionary notes and with regard to alterations of progenitor cell hierarchies in response to low-level injury.
Russell W Smith; Douglas A Hicks; Susan D Reynolds
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  46     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-02-06     Completed Date:  2012-05-03     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  115-24     Citation Subset:  IM    
Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA.
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MeSH Terms
Bronchi / drug effects,  metabolism
Cell Differentiation / drug effects,  genetics
Doxycycline / pharmacology*
Epithelial Cells / cytology,  drug effects,  metabolism
Gene Expression / drug effects,  genetics
Stem Cells / cytology,  metabolism
Tetracycline / pharmacology
Trachea / cytology,  drug effects*,  metabolism*
Trans-Activators / pharmacology
Transgenes / drug effects,  genetics
beta Catenin / genetics,  metabolism,  physiology*
Grant Support
Reg. No./Substance:
0/Trans-Activators; 0/beta Catenin; 564-25-0/Doxycycline; 60-54-8/Tetracycline; EC 2.7.7.-/Cre recombinase; EC 2.7.7.-/Integrases

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