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PMID:24191021

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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

Significance

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

Notes

See also

References

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