title: Foxm1 transcription factor is critical for proliferation and differentiation of Clara cells during development of conducting airways.
abstract: Respiratory epithelial cells are derived from cell progenitors in the foregut endoderm that subsequently differentiate into the distinct cell types lining the conducting and alveolar regions of the lung. To identify transcriptional mechanisms regulating differentiation and maintenance of respiratory epithelial cells, we conditionally deleted Foxm1 transcription factor from the conducting airways of the developing mouse lung. Conditional deletion of Foxm1 from Clara cells, controlled by the Scgb1a1 promoter, dramatically altered airway structure and caused peribronchial fibrosis, resulting in airway hyperreactivity in adult mice. Deletion of Foxm1 inhibited proliferation of Clara cells and disrupted the normal patterning of epithelial cell differentiation in the bronchioles, causing squamous and goblet cell metaplasia, and the loss of Clara and ciliated cells. Surprisingly, conducting airways of Foxm1-deficient mice contained highly differentiated cuboidal type II epithelial cells that are normally restricted to the alveoli. Lineage tracing studies showed that the ectopic alveolar type II cells in Foxm1-deficient airways were derived from Clara cells. Deletion of Foxm1 inhibited Sox2 and Scgb1a1, both of which are critical for differentiation and function of Clara cells. In co-transfection experiments, Foxm1 directly bound to and induced transcriptional activity of Scgb1a1 and Sox2 promoters. Foxm1 is required for differentiation and maintenance of epithelial cells lining conducting airways.
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ustiyan
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wert
authors.forename: Machiko
authors.initials: M
authors.lastname: Ikegami
authors.forename: I-Ching
authors.initials: IC
authors.lastname: Wang
authors.forename: Tanya V
authors.initials: TV
authors.lastname: Kalin
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kalinichenko
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D008168:Lung / Q000166:cytology / Q000254:growth & development; D051379:Mice; D011650:Pulmonary Alveoli / Q000166:cytology; D012137:Respiratory System / Q000166:cytology* / Q000254:growth & development*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D014598:Uteroglobin / Q000378:metabolism
chemical_list: D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D055748:SOXB1 Transcription Factors; C556390:Scgb1a1 protein, mouse; C527783:Sox2 protein, mouse; D014598:Uteroglobin