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Sox17 promotes cell cycle progression and inhibits TGF-beta/Smad3 signaling to initiate progenitor cell behavior in the respiratory epithelium.

Lange AW, Keiser AR, Wells JM, Zorn AM, Whitsett JA - PLoS ONE (2009)

Bottom Line: Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro.Sox17 decreased the expression of transforming growth factor-beta (TGF-beta)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-beta1-mediated transcriptional responses in vitro.Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

ABSTRACT
The Sry-related high mobility group box transcription factor Sox17 is required for diverse developmental processes including endoderm formation, vascular development, and fetal hematopoietic stem cell maintenance. Expression of Sox17 in mature respiratory epithelial cells causes proliferation and lineage respecification, suggesting that Sox17 can alter adult lung progenitor cell fate. In this paper, we identify mechanisms by which Sox17 influences lung epithelial progenitor cell behavior and reprograms cell fate in the mature respiratory epithelium. Conditional expression of Sox17 in epithelial cells of the adult mouse lung demonstrated that cell cluster formation and respecification of alveolar progenitor cells toward proximal airway lineages were rapidly reversible processes. Prolonged expression of Sox17 caused the ectopic formation of bronchiolar-like structures with diverse respiratory epithelial cell characteristics in alveolar regions of lung. During initiation of progenitor cell behavior, Sox17 induced proliferation and increased the expression of the progenitor cell marker Sca-1 and genes involved in cell cycle progression. Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro. Sox17 decreased the expression of transforming growth factor-beta (TGF-beta)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-beta1-mediated transcriptional responses in vitro. Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity. Together, these data show that a subset of mature respiratory epithelial cells retains remarkable phenotypic plasticity and that Sox17, a gene required for early endoderm formation, activates the cell cycle and reinitiates multipotent progenitor cell behavior in mature lung cells.

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Sox17 induces proliferation of respiratory epithelial cells in the adult mouse lung.Immunohistochemistry was performed on lung sections from adult CCSPrtTA control (A–C; G–I) and CCSPrtTA/tetO-Sox17 (D–F; J–L) transgenic mice after treatment with Dox for 1, 3, and 5 days (d). (A–F) Immunostaining shows endogenous expression of Sox17 in endothelial cells and Sox17 transgene expression in bronchioles and alveolar type II cells (D–F). Hyperplastic cell clusters are evident by 5 d (arrow and inset, F). (G–L) Phospho-histone H3 immunostaining shows respiratory epithelial cell proliferation after 3 d of Dox treatment in Sox17 transgenic mice. Proliferative cells were detected in the peripheral lung (K–L; arrow and inset) and bronchioles (K–L; arrowhead). (M–O) Colocalization of Sox17 (M) and phospho-histone H3 (pHH3; N) is shown by dual-label immunofluorescence after 5 d Dox exposure. Nuclei are stained with DAPI (O; blue). Scale bars, 50 µm.
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pone-0005711-g003: Sox17 induces proliferation of respiratory epithelial cells in the adult mouse lung.Immunohistochemistry was performed on lung sections from adult CCSPrtTA control (A–C; G–I) and CCSPrtTA/tetO-Sox17 (D–F; J–L) transgenic mice after treatment with Dox for 1, 3, and 5 days (d). (A–F) Immunostaining shows endogenous expression of Sox17 in endothelial cells and Sox17 transgene expression in bronchioles and alveolar type II cells (D–F). Hyperplastic cell clusters are evident by 5 d (arrow and inset, F). (G–L) Phospho-histone H3 immunostaining shows respiratory epithelial cell proliferation after 3 d of Dox treatment in Sox17 transgenic mice. Proliferative cells were detected in the peripheral lung (K–L; arrow and inset) and bronchioles (K–L; arrowhead). (M–O) Colocalization of Sox17 (M) and phospho-histone H3 (pHH3; N) is shown by dual-label immunofluorescence after 5 d Dox exposure. Nuclei are stained with DAPI (O; blue). Scale bars, 50 µm.

Mentions: To assess the molecular mechanisms by which Sox17 initiates cell cluster formation in respiratory epithelial progenitor cells, Sox17 was conditionally expressed in adult CCSPrtTA/tetO-Sox17 mice for 1, 3, or 5 days. Endogenous expression of Sox17 was detected in endothelial cells in the peripheral lung but not in airway epithelial cells. In contrast, Sox17 staining was readily detected in bronchioles and alveolar type II cells of CCSPrtTA/tetO-Sox17 mice, consistent with sites of rtTA-directed gene expression in this mouse line (Fig. 3A–F) [33]. The formation of cell clusters in the alveolar regions was evident 5 days after the induction of Sox17 expression (Fig. 3F). Immunostaining for phospho-histone H3 revealed the presence of mitotic cells in the both the bronchioles and alveoli as early as 3 days following Sox17 expression (Fig. 3G–L), with a 4.7-fold increase in the number of proliferative cells compared to control lungs (Fig. S1). Phospho-histone H3 staining was also observed in a subset cells at the bronchoalveolar duct junctions in the lungs of CCSPrtTA/tetO-Sox17 mice (Fig. 3L; arrowhead). Although Sox17 expression and cell proliferation were detected in the bronchioles and bronchoalveolar duct junctions of CCSPrtTA/tetO-Sox17 mice, hyperplastic foci within these regions were not evident. Dual immunofluorescence revealed colocalized expression of phospho-histone H3 with Sox17, demonstrating that proliferation occurs within the Sox17-expressing population of cells in CCSPrtTA/tetO-Sox17 mice (Fig. 3M–O). Of the respiratory epithelial cells expressing Sox17, 28% coexpressed phospho-histone H3 (Fig. S1) and only a subset of alveolar type II cells expressing Sox17 formed cell clusters. Thus, Sox17 expression induces a subset of mature respiratory epithelial cells in the adult mouse lung to reenter the cell cycle, resulting in the formation of atypical cell clusters in the alveolar region within 5 days.


Sox17 promotes cell cycle progression and inhibits TGF-beta/Smad3 signaling to initiate progenitor cell behavior in the respiratory epithelium.

Lange AW, Keiser AR, Wells JM, Zorn AM, Whitsett JA - PLoS ONE (2009)

Sox17 induces proliferation of respiratory epithelial cells in the adult mouse lung.Immunohistochemistry was performed on lung sections from adult CCSPrtTA control (A–C; G–I) and CCSPrtTA/tetO-Sox17 (D–F; J–L) transgenic mice after treatment with Dox for 1, 3, and 5 days (d). (A–F) Immunostaining shows endogenous expression of Sox17 in endothelial cells and Sox17 transgene expression in bronchioles and alveolar type II cells (D–F). Hyperplastic cell clusters are evident by 5 d (arrow and inset, F). (G–L) Phospho-histone H3 immunostaining shows respiratory epithelial cell proliferation after 3 d of Dox treatment in Sox17 transgenic mice. Proliferative cells were detected in the peripheral lung (K–L; arrow and inset) and bronchioles (K–L; arrowhead). (M–O) Colocalization of Sox17 (M) and phospho-histone H3 (pHH3; N) is shown by dual-label immunofluorescence after 5 d Dox exposure. Nuclei are stained with DAPI (O; blue). Scale bars, 50 µm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2682659&req=5

pone-0005711-g003: Sox17 induces proliferation of respiratory epithelial cells in the adult mouse lung.Immunohistochemistry was performed on lung sections from adult CCSPrtTA control (A–C; G–I) and CCSPrtTA/tetO-Sox17 (D–F; J–L) transgenic mice after treatment with Dox for 1, 3, and 5 days (d). (A–F) Immunostaining shows endogenous expression of Sox17 in endothelial cells and Sox17 transgene expression in bronchioles and alveolar type II cells (D–F). Hyperplastic cell clusters are evident by 5 d (arrow and inset, F). (G–L) Phospho-histone H3 immunostaining shows respiratory epithelial cell proliferation after 3 d of Dox treatment in Sox17 transgenic mice. Proliferative cells were detected in the peripheral lung (K–L; arrow and inset) and bronchioles (K–L; arrowhead). (M–O) Colocalization of Sox17 (M) and phospho-histone H3 (pHH3; N) is shown by dual-label immunofluorescence after 5 d Dox exposure. Nuclei are stained with DAPI (O; blue). Scale bars, 50 µm.
Mentions: To assess the molecular mechanisms by which Sox17 initiates cell cluster formation in respiratory epithelial progenitor cells, Sox17 was conditionally expressed in adult CCSPrtTA/tetO-Sox17 mice for 1, 3, or 5 days. Endogenous expression of Sox17 was detected in endothelial cells in the peripheral lung but not in airway epithelial cells. In contrast, Sox17 staining was readily detected in bronchioles and alveolar type II cells of CCSPrtTA/tetO-Sox17 mice, consistent with sites of rtTA-directed gene expression in this mouse line (Fig. 3A–F) [33]. The formation of cell clusters in the alveolar regions was evident 5 days after the induction of Sox17 expression (Fig. 3F). Immunostaining for phospho-histone H3 revealed the presence of mitotic cells in the both the bronchioles and alveoli as early as 3 days following Sox17 expression (Fig. 3G–L), with a 4.7-fold increase in the number of proliferative cells compared to control lungs (Fig. S1). Phospho-histone H3 staining was also observed in a subset cells at the bronchoalveolar duct junctions in the lungs of CCSPrtTA/tetO-Sox17 mice (Fig. 3L; arrowhead). Although Sox17 expression and cell proliferation were detected in the bronchioles and bronchoalveolar duct junctions of CCSPrtTA/tetO-Sox17 mice, hyperplastic foci within these regions were not evident. Dual immunofluorescence revealed colocalized expression of phospho-histone H3 with Sox17, demonstrating that proliferation occurs within the Sox17-expressing population of cells in CCSPrtTA/tetO-Sox17 mice (Fig. 3M–O). Of the respiratory epithelial cells expressing Sox17, 28% coexpressed phospho-histone H3 (Fig. S1) and only a subset of alveolar type II cells expressing Sox17 formed cell clusters. Thus, Sox17 expression induces a subset of mature respiratory epithelial cells in the adult mouse lung to reenter the cell cycle, resulting in the formation of atypical cell clusters in the alveolar region within 5 days.

Bottom Line: Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro.Sox17 decreased the expression of transforming growth factor-beta (TGF-beta)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-beta1-mediated transcriptional responses in vitro.Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

ABSTRACT
The Sry-related high mobility group box transcription factor Sox17 is required for diverse developmental processes including endoderm formation, vascular development, and fetal hematopoietic stem cell maintenance. Expression of Sox17 in mature respiratory epithelial cells causes proliferation and lineage respecification, suggesting that Sox17 can alter adult lung progenitor cell fate. In this paper, we identify mechanisms by which Sox17 influences lung epithelial progenitor cell behavior and reprograms cell fate in the mature respiratory epithelium. Conditional expression of Sox17 in epithelial cells of the adult mouse lung demonstrated that cell cluster formation and respecification of alveolar progenitor cells toward proximal airway lineages were rapidly reversible processes. Prolonged expression of Sox17 caused the ectopic formation of bronchiolar-like structures with diverse respiratory epithelial cell characteristics in alveolar regions of lung. During initiation of progenitor cell behavior, Sox17 induced proliferation and increased the expression of the progenitor cell marker Sca-1 and genes involved in cell cycle progression. Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro. Sox17 decreased the expression of transforming growth factor-beta (TGF-beta)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-beta1-mediated transcriptional responses in vitro. Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity. Together, these data show that a subset of mature respiratory epithelial cells retains remarkable phenotypic plasticity and that Sox17, a gene required for early endoderm formation, activates the cell cycle and reinitiates multipotent progenitor cell behavior in mature lung cells.

Show MeSH
Related in: MedlinePlus