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PMID:15030764

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Citation

Bialek, P, Kern, B, Yang, X, Schrock, M, Sosic, D, Hong, N, Wu, H, Yu, K, Ornitz, DM, Olson, EN, Justice, MJ and Karsenty, G (2004) A twist code determines the onset of osteoblast differentiation. Dev. Cell 6:423-35

Abstract

Runx2 is necessary and sufficient for osteoblast differentiation, yet its expression precedes the appearance of osteoblasts by 4 days. Here we show that Twist proteins transiently inhibit Runx2 function during skeletogenesis. Twist-1 and -2 are expressed in Runx2-expressing cells throughout the skeleton early during development, and osteoblast-specific gene expression occurs only after their expression decreases. Double heterozygotes for Twist-1 and Runx2 deletion have none of the skull abnormalities observed in Runx2(+/-) mice, a Twist-2 null background rescues the clavicle phenotype of Runx2(+/-) mice, and Twist-1 or -2 deficiency leads to premature osteoblast differentiation. Furthermore, Twist-1 overexpression inhibits osteoblast differentiation without affecting Runx2 expression. Twist proteins' antiosteogenic function is mediated by a novel domain, the Twist box, which interacts with the Runx2 DNA binding domain to inhibit its function. In vivo mutagenesis confirms the antiosteogenic function of the Twist box. Thus, relief of inhibition by Twist proteins is a mandatory event precluding osteoblast differentiation.

Links

PubMed

Keywords

Aging/metabolism; Animals; Animals, Newborn; Blotting, Northern/methods; Blotting, Western/methods; Cell Differentiation/physiology; Cells, Cultured; Cercopithecus aethiops; Core Binding Factor Alpha 1 Subunit; DNA Mutational Analysis/methods; Electrophoretic Mobility Shift Assay/methods; Embryo, Mammalian; Gene Expression Regulation/physiology; Heterozygote; In Situ Hybridization; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myogenic Regulatory Factors/genetics; Myogenic Regulatory Factors/physiology; Neoplasm Proteins/metabolism; Nuclear Proteins/deficiency; Nuclear Proteins/genetics; Nuclear Proteins/physiology; Osteoblasts/physiology; Osteogenesis/physiology; Precipitin Tests/methods; Proline/genetics; Protein Structure, Tertiary/physiology; RNA/analysis; Rats; Repressor Proteins/genetics; Repressor Proteins/physiology; Serine/genetics; Skeleton; Staining and Labeling; Transcription Factors/deficiency; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription Factors/physiology; Transcriptional Activation/physiology; Transfection/methods; Twist Transcription Factor

Significance

Annotations

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

RAT:OSTCN

located_in

GO:0005576: extracellular region

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TWST1

acts_upstream_of_or_within

GO:0030326: embryonic limb morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3038818

P

Seeded From UniProt

complete

MOUSE:TWST1

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3038818

P

Seeded From UniProt

complete

MOUSE:TWST1

enables

GO:0019904: protein domain specific binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q08775

F

Seeded From UniProt

complete

MOUSE:TWST1

acts_upstream_of_or_within

GO:0001649: osteoblast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857265
MGI:MGI:3038818

P

Seeded From UniProt

complete

MOUSE:TWST1

acts_upstream_of_or_within

GO:0001503: ossification

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3038818

P

Seeded From UniProt

complete

MOUSE:TWST1

acts_upstream_of_or_within

GO:0048704: embryonic skeletal system morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3038818

P

Seeded From UniProt

complete

MOUSE:TWST1

acts_upstream_of_or_within

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:99829

P

Seeded From UniProt

complete

MOUSE:TWST1

acts_upstream_of_or_within

GO:0060363: cranial suture morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857265
MGI:MGI:3038818

P

Seeded From UniProt

complete

MOUSE:TWST1

acts_upstream_of_or_within

GO:0045668: negative regulation of osteoblast differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TWST1

acts_upstream_of_or_within

GO:0044092: negative regulation of molecular function

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TWST1

acts_upstream_of_or_within

GO:0042733: embryonic digit morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3038818

P

Seeded From UniProt

complete

MOUSE:OSTCN

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:OSTCN

located_in

GO:0005576: extracellular region

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P04640

C

Seeded From UniProt

complete

MOUSE:RUNX2

enables

GO:0019904: protein domain specific binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P26687
PR:Q9D030

F

Seeded From UniProt

complete

MOUSE:RUNX2

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RUNX2

acts_upstream_of_or_within

GO:0048705: skeletal system morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176465

P

Seeded From UniProt

complete

MOUSE:RUNX2

acts_upstream_of_or_within

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:104685
MGI:MGI:98872

P

Seeded From UniProt

complete

MOUSE:RUNX2

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

Seeded From UniProt

complete

MOUSE:TWST2

enables

GO:0019904: protein domain specific binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q08775

F

Seeded From UniProt

complete

MOUSE:TWST2

acts_upstream_of_or_within

GO:0001649: osteoblast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3044412

P

Seeded From UniProt

complete

MOUSE:TWST2

acts_upstream_of_or_within

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:99829

P

Seeded From UniProt

complete

MOUSE:TWST2

acts_upstream_of_or_within

GO:0045668: negative regulation of osteoblast differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3044412

P

Seeded From UniProt

complete

MOUSE:TWST2

acts_upstream_of_or_within

GO:0044092: negative regulation of molecular function

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CREB1

enables

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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