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PMID:18824566

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Citation

Wang, X, Pasolli, HA, Williams, T and Fuchs, E (2008) AP-2 factors act in concert with Notch to orchestrate terminal differentiation in skin epidermis. J. Cell Biol. 183:37-48

Abstract

The mechanisms by which mammalian epidermal stem cells cease to proliferate and embark upon terminal differentiation are still poorly understood. By conditionally ablating two highly expressed transcription factors, AP-2alpha and AP-2gamma, we unmasked functional redundancies and discovered an essential role for AP-2s in the process. In vivo and in vitro, AP-2 deficiency is accompanied by surprisingly minimal changes in basal gene expression but severely perturbed terminal differentiation and suppression of additional transcription factors and structural genes involved. In dissecting the underlying molecular pathways, we uncover parallel pathways involving AP-2 and Notch signaling, which converge to govern CCAAT/enhancer binding protein genes and orchestrate the transition from basal proliferation to suprabasal differentiation. Finally, we extend the striking similarities in compromising either Notch signaling or AP-2alpha/AP-2gamma in developing skin to that in postnatal skin, where all hair follicles and sebaceous gland differentiation are also repressed and overt signs of premalignant conversion emerge.

Links

PubMed PMC2557040 Online version:10.1083/jcb.200804030

Keywords

Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors/genetics; CCAAT-Enhancer-Binding Proteins/genetics; CCAAT-Enhancer-Binding Proteins/metabolism; Cell Cycle Proteins/genetics; Cell Differentiation/physiology; Cell Proliferation; Embryo, Mammalian/abnormalities; Embryo, Mammalian/metabolism; Epidermis/abnormalities; Epidermis/metabolism; Epidermis/ultrastructure; Gene Expression Regulation, Developmental; Hair Follicle/abnormalities; Hair Follicle/metabolism; Homeodomain Proteins/genetics; Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics; Keratins/genetics; Keratins/metabolism; Mice; Mice, Knockout; Mice, Nude; Mice, Transgenic; Microscopy, Electron; Receptors, Notch/genetics; Receptors, Notch/physiology; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction/physiology; Skin/embryology; Skin/metabolism; Skin Transplantation; Transcription Factor AP-2/genetics; Transcription Factor AP-2/physiology; Transglutaminases/genetics; Transglutaminases/metabolism

Significance

Annotations

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

MOUSE:CEBPB

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000312)
  • part_of:(EMAPA:17528)

Seeded From UniProt

complete

MOUSE:AP2A

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000066)
  • part_of:(EMAPA:32779)|part_of:(CL:0000066)
  • part_of:(EMAPA:32785)

Seeded From UniProt

complete

MOUSE:AP2A

acts_upstream_of_or_within

GO:0003334: keratinocyte development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:106032

P

  • occurs_in:(EMAPA:32785)
  • results_in_development_of:(CL:0000312)|occurs_in(EMAPA:32786)
  • results_in_development_of:(CL:0000312)|occurs_in(EMAPA:32787)
  • results_in_development_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:AP2A

acts_upstream_of_or_within

GO:0043588: skin development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:106032

P

  • results_in_development_of:(EMAPA:32785)|results_in_development_of:(EMAPA:32786)|results_in_development_of:(EMAPA:32787)

Seeded From UniProt

complete

MOUSE:CEBPA

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000312)
  • part_of:(EMAPA:17528)

Seeded From UniProt

complete

MOUSE:AP2C

acts_upstream_of_or_within

GO:0001942: hair follicle development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104671

P

  • results_in_development_of:(EMAPA:18771)

Seeded From UniProt

complete

MOUSE:AP2C

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000066)
  • part_of:(EMAPA:32779)|part_of:(CL:0000066)
  • part_of:(EMAPA:32785)

Seeded From UniProt

complete

MOUSE:AP2C

acts_upstream_of_or_within

GO:0003334: keratinocyte development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104671

P

  • occurs_in:(EMAPA:32785)
  • results_in_development_of:(CL:0000312)|occurs_in(EMAPA:32786)
  • results_in_development_of:(CL:0000312)|occurs_in(EMAPA:32787)
  • results_in_development_of:(CL:0000312)

Seeded From UniProt

complete

MOUSE:AP2C

acts_upstream_of_or_within

GO:0048733: sebaceous gland development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104671

P

  • results_in_development_of:(EMAPA:36582)

Seeded From UniProt

complete

MOUSE:AP2C

acts_upstream_of_or_within

GO:0043588: skin development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104671

P

  • results_in_development_of:(EMAPA:32785)|results_in_development_of:(EMAPA:32786)|results_in_development_of:(EMAPA:32787)

Seeded From UniProt

complete

MOUSE:CEBPA

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17528)
  • part_of:(CL:0000312)

Seeded From UniProt

complete


See also

References

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