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PMID:11694877

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Citation

Bamforth, SD, Bragança, J, Eloranta, JJ, Murdoch, JN, Marques, FI, Kranc, KR, Farza, H, Henderson, DJ, Hurst, HC and Bhattacharya, S (2001) Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. Nat. Genet. 29:469-74

Abstract

The protein EP300 and its paralog CREBBP (CREB-binding protein) are ubiquitously expressed transcriptional co-activators and histone acetyl transferases. The gene EP300 is essential for normal cardiac and neural development, whereas CREBBP is essential for neurulation, hematopoietic differentiation, angiogenesis and skeletal and cardiac development. Mutations in CREBBP cause Rubinstein-Taybi syndrome, which is characterized by mental retardation, skeletal abnormalities and congenital cardiac defects. The CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) binds EP300 and CREBBP with high affinity and regulates gene transcription. Here we show that Cited2-/- embryos die with cardiac malformations, adrenal agenesis, abnormal cranial ganglia and exencephaly. The cardiac defects include atrial and ventricular septal defects, overriding aorta, double-outlet right ventricle, persistent truncus arteriosus and right-sided aortic arches. We find increased apoptosis in the midbrain region and a marked reduction in ErbB3-expressing neural crest cells in mid-embryogenesis. We show that CITED2 interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2). Transactivation by TFAP2 isoforms is defective in Cited2-/- embryonic fibroblasts and is rescued by ectopically expressed CITED2. As certain Tfap2 isoforms are essential in neural crest, neural tube and cardiac development, we propose that abnormal embryogenesis in mice lacking Cited2 results, at least in part, from its role as a Tfap2 co-activator.

Links

PubMed Online version:10.1038/ng768

Keywords

Adrenal Glands/abnormalities; Adrenal Glands/embryology; Animals; Cell Line; DNA-Binding Proteins/metabolism; Female; Heart Defects, Congenital/genetics; Male; Mice; Mice, Knockout; Neural Crest/abnormalities; Neural Tube Defects/genetics; Repressor Proteins; Trans-Activators/genetics; Trans-Activators/physiology; Transcription Factor AP-2; Transcription Factors/metabolism

Significance

Annotations

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

MOUSE:CITE2

acts_upstream_of_or_within

GO:0030325: adrenal gland development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2179740

P

  • results_in_development_of:(EMAPA:16039)

Seeded From UniProt

complete

MOUSE:CITE2

acts_upstream_of_or_within

GO:0021602: cranial nerve morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2179740

P

Seeded From UniProt

complete

MOUSE:CITE2

acts_upstream_of_or_within

GO:0001841: neural tube formation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2179740

P

  • results_in_formation_of:(EMAPA:16039)

Seeded From UniProt

complete

MOUSE:CITE2

acts_upstream_of_or_within

GO:0007422: peripheral nervous system development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2179740

P

  • results_in_development_of:(EMAPA:16668)

Seeded From UniProt

complete

MOUSE:CITE2

acts_upstream_of_or_within

GO:0003151: outflow tract morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2179740

P

Seeded From UniProt

complete

MOUSE:CITE2

enables

GO:0003713: transcription coactivator activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:CITE2

acts_upstream_of_or_within

GO:0061308: cardiac neural crest cell development involved in heart development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2179740

P

  • occurs_in:(EMAPA:16039)

Seeded From UniProt

complete

MOUSE:CITE2

acts_upstream_of_or_within

GO:0060411: cardiac septum morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2179740

P

Seeded From UniProt

complete

MOUSE:CITE2

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P34056
PR:Q61312
PR:Q61313

F

Seeded From UniProt

complete

HUMAN:AP2A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99967

F

Seeded From UniProt

complete

MOUSE:AP2A

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:AP2C

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:AP2B

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:AP2B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99967

F

Seeded From UniProt

complete

HUMAN:AP2C

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99967

F

Seeded From UniProt

complete

HUMAN:CITE2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92481

F

Seeded From UniProt

complete

HUMAN:CITE2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P05549

F

Seeded From UniProt

complete

HUMAN:CITE2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92754

F

Seeded From UniProt

complete

HUMAN:CITE2

enables

GO:0003713: transcription coactivator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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