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PMID:19224984

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Citation

Retting, KN, Song, B, Yoon, BS and Lyons, KM (2009) BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development 136:1093-104

Abstract

Bone morphogenetic protein (BMP) signaling is required for endochondral bone formation. However, whether or not the effects of BMPs are mediated via canonical Smad pathways or through noncanonical pathways is unknown. In this study we have determined the role of receptor Smads 1, 5 and 8 in chondrogenesis. Deletion of individual Smads results in viable and fertile mice. Combined loss of Smads 1, 5 and 8, however, results in severe chondrodysplasia. Smad1/5(CKO) (cartilage-specific knockout) mutant mice are nearly identical to Smad1/5(CKO);Smad8(-/-) mutants, indicating that Smads 1 and 5 have overlapping functions and are more important than Smad8 in cartilage. The Smad1/5(CKO) phenotype is more severe than that of Smad4(CKO) mice, challenging the dogma, at least in chondrocytes, that Smad4 is required to mediate Smad signaling through BMP pathways. The chondrodysplasia in Smad1/5(CKO) mice is accompanied by imbalances in cross-talk between the BMP, FGF and Ihh/PTHrP pathways. We show that Ihh is a direct target of BMP pathways in chondrocytes, and that FGF exerts antagonistic effects on Ihh expression. Finally, we tested whether FGF exerts its antagonistic effects directly through Smad linker phosphorylation. The results support the alternative conclusion that the effects of FGFs on BMP signaling are indirect in vivo.

Links

PubMed PMC2668702 Online version:10.1242/dev.029926

Keywords

Animals; Bone Morphogenetic Proteins/physiology; Cell Differentiation; Cell Proliferation; Cell Survival; Chondrocytes/cytology; Chondrocytes/physiology; Chondrogenesis/genetics; Chondrogenesis/physiology; Extremities/embryology; Female; Fibroblast Growth Factors/physiology; Hedgehog Proteins/physiology; Male; Mice; Mice, Knockout; Mice, Mutant Strains; Osteogenesis/genetics; Osteogenesis/physiology; Parathyroid Hormone-Related Protein/physiology; Phosphorylation; Signal Transduction; Smad1 Protein/deficiency; Smad1 Protein/genetics; Smad1 Protein/physiology; Smad4 Protein/deficiency; Smad4 Protein/genetics; Smad4 Protein/physiology; Smad5 Protein/deficiency; Smad5 Protein/genetics; Smad5 Protein/physiology; Smad8 Protein/deficiency; Smad8 Protein/genetics; Smad8 Protein/physiology

Significance

Annotations

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

MOUSE:SMAD9

acts_upstream_of_or_within

GO:0030509: BMP signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:109452
MGI:MGI:1328787

P

Seeded From UniProt

complete

MOUSE:SMAD9

acts_upstream_of_or_within

GO:0051216: cartilage development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:109452
MGI:MGI:1328787

P

Seeded From UniProt

complete

MOUSE:SMAD9

acts_upstream_of_or_within

GO:0060348: bone development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:109452
MGI:MGI:1328787

P

Seeded From UniProt

complete

MOUSE:SMAD1

acts_upstream_of_or_within

GO:0030509: BMP signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1328787
MGI:MGI:1859993

P

Seeded From UniProt

complete

MOUSE:SMAD1

acts_upstream_of_or_within

GO:0051216: cartilage development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1328787
MGI:MGI:1859993

P

Seeded From UniProt

complete

MOUSE:SMAD1

acts_upstream_of_or_within

GO:0060348: bone development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1328787
MGI:MGI:1859993

P

Seeded From UniProt

complete

MOUSE:SMAD5

acts_upstream_of_or_within

GO:0030509: BMP signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:109452
MGI:MGI:1859993

P

Seeded From UniProt

complete

MOUSE:SMAD5

acts_upstream_of_or_within

GO:0051216: cartilage development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:109452
MGI:MGI:1859993

P

Seeded From UniProt

complete

MOUSE:SMAD5

acts_upstream_of_or_within

GO:0060348: bone development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:109452
MGI:MGI:1859993

P

Seeded From UniProt

complete


See also

References

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