Document Detail


Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2.
MedLine Citation:
PMID:  22675208     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The molecular pathways regulating cell lineage determination and regeneration in epithelial tissues are poorly understood. The secretory epithelium of the lung is required for production of mucus to help protect the lung against environmental insults, including pathogens and pollution, that can lead to debilitating diseases such as asthma and chronic obstructive pulmonary disease. We show that the transcription factors Foxp1 and Foxp4 act cooperatively to regulate lung secretory epithelial cell fate and regeneration by directly restricting the goblet cell lineage program. Loss of Foxp1/4 in the developing lung and in postnatal secretory epithelium leads to ectopic activation of the goblet cell fate program, in part, through de-repression of the protein disulfide isomerase anterior gradient 2 (Agr2). Forced expression of Agr2 is sufficient to promote the goblet cell fate in the developing airway epithelium. Finally, in a model of lung secretory cell injury and regeneration, we show that loss of Foxp1/4 leads to catastrophic loss of airway epithelial regeneration due to default differentiation of secretory cells into the goblet cell lineage. These data demonstrate the importance of Foxp1/4 in restricting cell fate choices during development and regeneration, thereby providing the proper balance of functional epithelial lineages in the lung.
Authors:
Shanru Li; Yi Wang; Yuzhen Zhang; Min Min Lu; Francesco J DeMayo; Joseph D Dekker; Philip W Tucker; Edward E Morrisey
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-06-06
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  139     ISSN:  1477-9129     ISO Abbreviation:  Development     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-27     Completed Date:  2012-09-04     Revised Date:  2013-12-05    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  2500-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Southern
Cell Differentiation / genetics,  physiology
Chromatin Immunoprecipitation
Forkhead Transcription Factors / genetics,  metabolism*
Goblet Cells / metabolism
Lung / metabolism*
Mice
Mice, Inbred C57BL
Mucoproteins / genetics,  metabolism*
Oligonucleotide Array Sequence Analysis
Polymerase Chain Reaction
Regeneration / physiology
Repressor Proteins / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
P30 AR057217/AR/NIAMS NIH HHS; R01 CA31534/CA/NCI NIH HHS; R01 HL071589/HL/NHLBI NIH HHS; R01 HL071589/HL/NHLBI NIH HHS; R01 HL087825/HL/NHLBI NIH HHS; U01 HL110942/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Agr2 protein, mouse; 0/Forkhead Transcription Factors; 0/Foxp1 protein, mouse; 0/Foxp4 protein, mouse; 0/Mucoproteins; 0/Repressor Proteins
Comments/Corrections

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