title: Sox2 regulates the emergence of lung basal cells by directly activating the transcription of Trp63.
abstract: Lung development is determined by the coordinated expression of several key genes. Previously, we and others have shown the importance of the sex determining region Y-box 2 (Sox2) gene in lung development. Transgenic expression of Sox2 during lung development resulted in cystic airways, and here we show that modulating the timing of ectopic Sox2 expression in the branching regions of the developing lung results in variable cystic lesions resembling the spectrum of the human congenital disorder congenital cystic adenomatoid malformation (CCAM). Sox2 dominantly differentiated naive epithelial cells into the proximal lineage irrespective of the presence of Fgf10. Sox2 directly induced the expression of Trp63, the master switch toward the basal cell lineage and induced the expression of Gata6, a factor involved in the emergence of bronchoalveolar stem cells. We showed that SOX2 and TRP63 are coexpressed in the lungs of human patients with type II CCAM. The combination of premature differentiation toward the proximal cell lineage and the induction of proliferation resulted in the cyst-like structures. Thus, we show that Sox2 is directly responsible for the emergence of two lung progenitor cells: basal cells by regulating the master gene Trp63 and bronchoalveolar stem cells by regulating Gata6.
authors.affiliation: Departments of 1 Pediatric Surgery of the Erasmus MC-Sophia Children's Hospital.
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Ochieng
authors.forename: Kim
authors.initials: K
authors.lastname: Schilders
authors.forename: Heleen
authors.initials: H
authors.lastname: Kool
authors.forename: Anne
authors.initials: A
authors.lastname: Boerema-De Munck
authors.forename: Marjon
authors.initials: M
authors.lastname: Buscop-Van Kempen
authors.forename: Cristina
authors.initials: C
authors.lastname: Gontan
authors.forename: Ron
authors.initials: R
authors.lastname: Smits
authors.forename: Frank G
authors.initials: FG
authors.lastname: Grosveld
authors.forename: Rene M H
authors.initials: RM
authors.lastname: Wijnen
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: Rottier
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D015615:Cystic Adenomatoid Malformation of Lung, Congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005865:Gestational Age; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D046509:Tissue Culture Techniques; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse; D010750:Phosphoproteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins
keywords: Sox2; Trp63; basal cells; bronchoalveolar stem cell; lung