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PMID:22072979

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Citation

Nowell, CS, Bredenkamp, N, Tetélin, S, Jin, X, Tischner, C, Vaidya, H, Sheridan, JM, Stenhouse, FH, Heussen, R, Smith, AJ and Blackburn, CC (2011) Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sublineage divergence. PLoS Genet. 7:e1002348

Abstract

The forkhead transcription factor Foxn1 is indispensable for thymus development, but the mechanisms by which it mediates thymic epithelial cell (TEC) development are poorly understood. To examine the cellular and molecular basis of Foxn1 function, we generated a novel and revertible hypomorphic allele of Foxn1. By varying levels of its expression, we identified a number of features of the Foxn1 system. Here we show that Foxn1 is a powerful regulator of TEC differentiation that is required at multiple intermediate stages of TE lineage development in the fetal and adult thymus. We find no evidence for a role for Foxn1 in TEC fate-choice. Rather, we show it is required for stable entry into both the cortical and medullary TEC differentiation programmes and subsequently is needed at increasing dosage for progression through successive differentiation states in both cortical and medullary TEC. We further demonstrate regulation by Foxn1 of a suite of genes with diverse roles in thymus development and/or function, suggesting it acts as a master regulator of the core thymic epithelial programme rather than regulating a particular aspect of TEC biology. Overall, our data establish a genetics-based model of cellular hierarchies in the TE lineage and provide mechanistic insight relating titration of a single transcription factor to control of lineage progression. Our novel revertible hypomorph system may be similarly applied to analyzing other regulators of development.

Links

PubMed PMC3207875 Online version:10.1371/journal.pgen.1002348

Keywords

Adrenal Medulla/cytology; Adrenal Medulla/metabolism; Alleles; Animals; Cell Differentiation/genetics; Cell Lineage/genetics; Embryonic Development/genetics; Epithelial Cells/metabolism; Epithelial Cells/physiology; Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism; Gene Expression Regulation, Developmental; Integrases/chemistry; Integrases/genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Tamoxifen/chemistry; Thymus Gland/growth & development

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:IL2RA

located_in

GO:0009897: external side of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CD8A

located_in

GO:0009897: external side of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CD4

located_in

GO:0009897: external side of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PTPRC

located_in

GO:0071944: cell periphery

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CD44

located_in

GO:0009897: external side of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FOXN1

acts_upstream_of_or_within

GO:0002260: lymphocyte homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5297717

P

Seeded From UniProt

complete

MOUSE:FOXN1

acts_upstream_of_or_within

GO:0033081: regulation of T cell differentiation in thymus

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5297717

P

Seeded From UniProt

complete

MOUSE:FOXN1

acts_upstream_of_or_within

GO:0008544: epidermis development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5297717

P

Seeded From UniProt

complete

MOUSE:FOXN1

acts_upstream_of_or_within

GO:0048538: thymus development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5297717

P

Seeded From UniProt

complete

MOUSE:PANK1

located_in

GO:0071944: cell periphery

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PLET1

located_in

GO:0009897: external side of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CD4

part_of

GO:0009897: external side of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CD44

part_of

GO:0009897: external side of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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