The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGFβ superfamily

Kingsley, David M.; Bland, Adrienne E.; Grubber, Janet M.; Marker, Paul C.; Russell, Liane B.; Copeland, Neal G.; Jenkins, Nancy A.

doi:10.1016/0092-8674(92)90510-j

Cited by 453 publications

(209 citation statements)

References 51 publications

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“…In mice with short ear mutations Bmp5 gene was disrupted. Mutations in the Bmp5 gene are associated with a wide range of skeletal defects, including reductions in long bone width and the size of several vertebral processes and an overall lower body mass (Kingsley et al, 1992;Mikic et al, 1995). Mutations in growth/ differentiation factor-5 (Gdf5 and CDMP-1) gene result in brachypodism in mice (Storm et al, 1994) and chondrodysplasia in humans (Thomas et al, 1996(Thomas et al, , 1997.…”

Section: Naturally Occurring Mutations In Bmps and Bmp Receptorsmentioning

confidence: 99%

The BMP signaling and in vivo bone formation

Cao

Chen

2005

Gene

272

197

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Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the transforming growth factor β(TGFβ) superfamily. The roles of BMPs in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. Signal transduction studies have revealed that Smads 1, 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and their signaling molecules have shown that BMP signaling plays critical roles in bone and cartilage development and postnatal bone formation. BMP activities are regulated at different molecular levels. Tissue-specific knockout of a specific BMP ligand, a subtype of BMP receptors or a specific signaling molecule is required to further determine the specific role of a BMP ligand, receptor or signaling molecule in a particular tissue.

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Section: Naturally Occurring Mutations In Bmps and Bmp Receptorsmentioning

confidence: 99%

The BMP signaling and in vivo bone formation

Cao

Chen

2005

Gene

272

197

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“…Immunolocalization and in situ hybridization studies suggest that BMPs/OPs are not only responsible for cartilage and bone formation in vivo, but may also influence overall cell differentiation and development of nonskeletal tissues (20)(21)(22)(23)(24)(25). Recombinant human OP-1 (rHuOP-1), also called recombinant human BMP-7, induces new bone formation in vivo with a specific activity comparable to that of highly purified natural bovine osteogenic preparations (26).…”

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confidence: 99%

Recombinant human osteogenic protein 1 is a potent stimulator of the synthesis of cartilage proteoglycans and collagens by human articular chondrocytes

Flechtenmacher

Huch

Thonar

et al. 1996

Arthritis & Rheumatism

229

150

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Objective. To study the effects of recombinant human osteogenic protein-1 (rHuOP-1; bone morphogenetic protein-7) on proteoglycan and collagen synthesis by human articular chondrocytes.Methods. Articular chondrocytes from fetal, adolescent, and adult human donors were cultured in alginate beads for 4 days in a mixture of Ham's F-12, Dulbecco's modified Eagle's medium, 10% fetal bovine serum (FBS), then for an additional 3-10 days in the presence and absence of rHuOP-1, with and without FBS. Chondrocyte synthetic activity was measured as the amount of incorporation of 35S-sulfate into proteoglycans and 3H-proline into hydroxyproline. Sieve chromatography and sodium dodecyl sulfatepolyacrylamide gel electrophoresis were performed to identify specific proteoglycans and collagens.Results. Recombinant human OP-1 markedly stimulated the synthesis of proteoglycans (mostly aggrecan) and collagens (predominantly type 11) by all chonSupported by NIH grants 2-P50-AR-39239 and AG-04736, an arthritis grant from Werk Kalle Albert (Hoechst AG, Germany), a fellowship from the German Academic Exchange Service (DAAD) (Dr. Huch), and a research fellowship from Opfermann AG, Germany (Dr. Flechtenmacher).Johannes Submitted for publication December 14, 1995; accepted in revised form June 10, 1996. drocyte preparations. This did not require the presence of FBS and was associated with continued expression of the chondrocyte phenotype.Conclusion. Recombinant human OP-1 is a more potent stimulator of the synthesis of cartilage-specific molecules by human articular chondrocytes than are other factors tested for comparison, including TGFPl and activin A.Bone morphogenetic proteins (BMPs), also called osteogenic proteins (OPs), were originally isolated from bone and were shown to induce new bone formation in the rat subcutaneous bone induction model (1-4). Several members of this family (BMPs 2-9) have been identified, and their corresponding genes cloned from human complementary DNA libraries (4-9). The amino acid sequences of these proteins show a highly conserved 7-cysteine domain at the C-terminal end, which suggests that they are members of the transfoming growth factor P (TGFP) superfamily, which includes

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“…Interestingly, BMP2 and BMP4 double heterozygous mice (Bmp2 +/− ;Bmp4 +/− ) have ventricular septal defects and abnormal valve structure after birth [53] and this suggests that the development of AVC cushions are sensitive to the dosage of BMP signalling. Complete knockouts of BMP5, BMP6, and BMP7 do not display defects in cardiac cushion formation [54][55][56]; however, BMP5/7 double knockout embryos lack cardiac cushions at E10.5 due to an overall hindrance in heart development [41]. The BMP6/7 double knockouts have defects in OFT cushions whereas the AVC cushions are not severely affected [42].…”

Section: Bmp Signalling In Cardiac Valve Developmentmentioning

confidence: 99%

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

Garside

Chang

Karsan

et al. 2012

Cell. Mol. Life Sci.

131

123

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Congenital heart defects affect approximately 1-5% of human newborns each year and of these cardiac defects, 20-30% are due to heart valve abnormalities. Recent literature indicates that key factors and pathways that regulate valve development are also implicated in congenital heart defects and valve disease. Currently, there are limited options for treatment of valve disease and therefore, having a better understanding of valve development can contribute critical insight into congenital valve defects and disease. There are three major signalling pathways required for early specification and initiation of Endothelial-to-Mesenchymal Transformation (EMT) in the cardiac cushions: BMP, TGFβ, and Notch signalling. BMPs secreted from the myocardium setup the environment for the overlying endocardium to become activated, Notch signalling initiates EMT, and both BMP and TGFβ signalling synergizes with Notch to promote the transition of endothelia to mesenchyme and to promote mesenchymal cell invasiveness. Together, these three essential signalling pathways help to form the cardiac cushions and populate them with mesenchyme and, consequently, set off the cascade of events required to develop mature heart valves. Furthermore, integration and cross-talk between these pathways generate highly stratified and delicate valve leaflets and septa of the heart. Here, we discuss BMP, TGFβ, and Notch signalling pathways during mouse cardiac cushion formation and how they together produce a coordinated EMT response in the developing mouse valves.

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The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGFβ superfamily

Cited by 453 publications

References 51 publications

The BMP signaling and in vivo bone formation

The BMP signaling and in vivo bone formation

Recombinant human osteogenic protein 1 is a potent stimulator of the synthesis of cartilage proteoglycans and collagens by human articular chondrocytes

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

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