PMID:24191021

Citation	Rockich, BE, Hrycaj, SM, Shih, HP, Nagy, MS, Ferguson, MA, Kopp, JL, Sander, M, Wellik, DM and Spence, JR (2013) Sox9 plays multiple roles in the lung epithelium during branching morphogenesis. Proc. Natl. Acad. Sci. U.S.A. 110:E4456-64
Abstract	Lung branching morphogenesis is a highly orchestrated process that gives rise to the complex network of gas-exchanging units in the adult lung. Intricate regulation of signaling pathways, transcription factors, and epithelial-mesenchymal cross-talk are critical to ensuring branching morphogenesis occurs properly. Here, we describe a role for the transcription factor Sox9 during lung branching morphogenesis. Sox9 is expressed at the distal tips of the branching epithelium in a highly dynamic manner as branching occurs and is down-regulated starting at embryonic day 16.5, concurrent with the onset of terminal differentiation of type 1 and type 2 alveolar cells. Using epithelial-specific genetic loss- and gain-of-function approaches, our results demonstrate that Sox9 controls multiple aspects of lung branching. Fine regulation of Sox9 levels is required to balance proliferation and differentiation of epithelial tip progenitor cells, and loss of Sox9 leads to direct and indirect cellular defects including extracellular matrix defects, cytoskeletal disorganization, and aberrant epithelial movement. Our evidence shows that unlike other endoderm-derived epithelial tissues, such as the intestine, Wnt/β-catenin signaling does not regulate Sox9 expression in the lung. We conclude that Sox9 collectively promotes proper branching morphogenesis by controlling the balance between proliferation and differentiation and regulating the extracellular matrix.
Links	PubMed PMC3839746 Online version:10.1073/pnas.1311847110
Keywords	Animals; Cell Differentiation/physiology; Cell Proliferation; Chromatin Immunoprecipitation; Doxycycline/pharmacology; Extracellular Matrix/metabolism; Flow Cytometry; Gene Expression Regulation, Developmental/genetics; Gene Expression Regulation, Developmental/physiology; Immunohistochemistry; In Situ Hybridization; Lung/cytology; Lung/embryology; Mice; Microscopy, Electron, Transmission; Organogenesis/physiology; Real-Time Polymerase Chain Reaction; Respiratory Mucosa/metabolism; Respiratory Mucosa/physiology; SOX9 Transcription Factor/metabolism; Tamoxifen/pharmacology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:KI67	located_in	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:CADH1	located_in	GO:0016323: basolateral plasma membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:FINC	located_in	GO:0005604: basement membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:PSPC	located_in	GO:0005737: cytoplasm	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:CO2A1	located_in	GO:0031012: extracellular matrix	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:ZO1	located_in	GO:0045177: apical part of cell	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:SOX2	located_in	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:PSPB	located_in	GO:0005737: cytoplasm	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:CTNB1	located_in	GO:0005911: cell-cell junction	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:SOX9	enables	GO:0097157: pre-mRNA intronic binding	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
MOUSE:SOX9	involved_in	GO:0098609: cell-cell adhesion	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:SOX9	involved_in	GO:0060487: lung epithelial cell differentiation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:SOX9	involved_in	GO:0061046: regulation of branching involved in lung morphogenesis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:SOX9	involved_in	GO:2000794: regulation of epithelial cell proliferation involved in lung morphogenesis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:SOX9	involved_in	GO:0010634: positive regulation of epithelial cell migration	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:SOX9	involved_in	GO:0030198: extracellular matrix organization	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:SOX9	involved_in	GO:0007010: cytoskeleton organization	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:DLG1	located_in	GO:0005604: basement membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:CRUM3	located_in	GO:0045177: apical part of cell	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:ERD21	located_in	GO:0005783: endoplasmic reticulum	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:CADH1	part_of	GO:0016323: basolateral plasma membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:CTNB1	part_of	GO:0005911: cell-cell junction	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:SOX2	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:KI67	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:ERD21	part_of	GO:0005783: endoplasmic reticulum	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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