Disease relevance of Bmp4

• Distribution of genes for bone morphogenetic protein-4, -6, growth differentiation factor-5, and bone morphogenetic protein receptors in the process of experimental spondylosis in mice [1].
• RESULTS: Mice overexpressing BMP4 in bone developed severe osteopenia with increased osteoclast number [2].
• We demonstrate that hypoxia accelerates the expression of Brachyury (a mesoderm-specific transcription factor), BMP4 (a mesoderm-promoting growth factor) and FLK1 (a marker of hemangioblasts, the bipotential progenitor of endothelial and hematopoietic cells) in differentiating ES cell cultures [3].
• Conversely, overexpression of BMP4 resulted in a significant decrease in the number of dorsal root ganglion neurons [4].
• Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype [5].
• Taken together these data demonstrate that SCF and hypoxia synergize with BMP4 to promote the expansion and differentiation of stress BFU-E during the recovery from acute anemia [6].

High impact information on Bmp4

• Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4 [7].
• To address the role of this factor, BMP-4-releasing agarose beads were added to dental mesenchyme in culture [8].
• Bone morphogenetic protein 4 (BMP-4), a member of the transforming growth factor beta superfamily, is expressed in the presumptive dental epithelium at the initiation of tooth development [8].
• Fgf8 expression was absent, and Bmp4 expression was expanded in the branchial-arch ectoderm [9].
• Secondly, Alk2-deficient embryos completely lacked PGCs and the heterozygotes had reduced numbers, resembling Bmp4-deficient phenotypes [10].

Chemical compound and disease context of Bmp4

• BMP-4 and retinoic acid synergistically induce activation of caspase-9 and cause apoptosis of P19 embryonal carcinoma cells cultured as a monolayer [11].

Biological context of Bmp4

• Thus, Bmp4 has 2 functions in the early morphogenesis of the kidney and urinary tract [12].
• Bmp4 heterozygous null mutant mice display, with high penetrance, abnormalities that mimic human congenital anomalies of the kidney and urinary tract (CAKUT), including hypo/dysplastic kidneys, hydroureter, ectopic ureterovesical (UV) junction, and double collecting system [12].
• These results show that, although latent, the early signaling pathways involved in odontogenesis remain inducible in Aves and suggest that loss of odontogenic Bmp4 expression may be responsible for the early arrest of tooth development in living birds [13].
• These experiments underscore the critical role of FRS2alpha in mediating multiple processes during embryonic development and reveal a potential new link between FGF and Bmp4 signaling pathways in early embryogenesis [14].
• A search for alterations of Shh downstream gene expression identified a dramatic shift of Bmp4 gene expression from the mesenchyme to the epithelium of the Shh mutant before GT outgrowth [15].

Anatomical context of Bmp4

• Here, we show that Bmp4, which is expressed strongly in the optic vesicle and weakly in the surrounding mesenchyme and surface ectoderm, has crucial roles during lens induction [16].
• Early expression of Islet1 in presumptive incisor epithelium is coincident with expression of Bmp4, which acts to induce Msx1 expression in the underlying mesenchyme [17].
• Additionally, Fgfr3 may coordinate the growth and differentiation of chondrocytes with the growth and differentiation of osteoprogenitor cells by simultaneously modulating Bmp4 and patched expression in both growth plate cartilage and in the perichondrium [18].
• Cartilage differentiation by Bmp4 treatment is reduced in cultured Cv2(-/-) fibroblasts [19].
• Furthermore, the expression of Fgf8 and Bmp4 in the dorsal midline of the telencephalon is altered [20].

Associations of Bmp4 with chemical compounds

• Well before exfoliation is evident, FimH-mediated attachment suppresses transforming growth factor-beta (Bmp4) and Wnt5a/Ca(2+) signaling to promote subsequent differentiation of basal/intermediate cells [21].
• These results suggest that AS-ODN against Bmp4 inhibited the differentiation and the site-specific proliferation of IEE cells in the occlusal region of molar tooth germs, resulting in the suppression of cusp formation [22].
• Treatment with BMP-4/7 and BMP-7 protein also enhanced Mfh1 expression in C1 cells [23].
• Consistent with this, antagonism of retinoid signaling phenocopies BMP4 action, whereas RA inhibits the chondrogenic stimulatory activity of BMP4 [24].
• Retinoic acid repression of bone morphogenetic protein 4 in inner ear development [25].

Physical interactions of Bmp4

• These data indicate that the extracellular domain of type I receptor for BMP-2 and BMP-4 is sufficient for high-affinity binding to its ligands and should prove useful in understanding the role of BMP-2/4 in vivo, because a suitable high-affinity anti-BMP antibody has yet to be developed [26].
• In an effort to understand how it selects its target genes we carried out a database search, and located several CP2 binding motifs in the promoter region of bone morphogenetic protein-4 (BMP4) [27].

Enzymatic interactions of Bmp4

• We also found that BMP4-induced differentiation of PGCs from epiblast in vitro was fully dependent on the existence of phosphorylated SMAD1 [28].
• BMP-4 time-dependently phosphorylated p70 S6 kinase [29].

Regulatory relationships of Bmp4

• FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development [30].
• Conversely, Bmp4 expression is upregulated in the perichondrium of Fgfr3-/- mice [18].
• In contrast, overexpression of Bmp4 in the wild type molar mesenchyme down-regulated Shh and Bmp2 expression in the enamel knot, the putative signaling center for tooth patterning, but did not produce a tooth phenotype [31].
• Bmp4 was expressed in the apical mesenchyme and Msx2 in the root sheath [32].
• Moreover, the defects in the vertebral column and eyes of the Cv2(-/-) mouse are substantially enhanced by deleting one copy of the Bmp4 gene, suggesting a pro-Bmp role of Cv2 in the development of these organs [19].

Other interactions of Bmp4

• However, the expression of three molecules involved in tooth initiation, Bmp4, Msx1, and Msx2, are absent from the presumptive chick dental lamina [13].
• The expression pattern of Bmp4 and Bmp7 suggest that these growth factors play an instructive role in specifying dorsoventral pattern in the limb [33].
• In the diencephalon of the mutant, Bmp4 expression is maintained, whereas Fgf8 expression is not detectable [34].
• Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis [35].
• Wnt10b, Bmp2 and Bmp4 continued to be expressed at this time, however [36].

Analytical, diagnostic and therapeutic context of Bmp4

• METHODS: Urogenital tissues obtained from Bmp4 heterozygous null mutant (Bmp4+/-) embryos at different stages, and metanephric and ureteral tissue explants cultured in the presence of recombinant BMP4 were subjected to morphologic, immunohistochemical and in situ hybridization analyses [37].
• Addition of Bmp4 to the medium surrounding lungs grown in organ culture stimulated cell proliferation and branching morphogenesis; however, direct injection of Bmp4 into the lung lumen had no effect on proliferation or branching [38].
• Chromatin immunoprecipitation assays further demonstrated that PBX proteins directly bind to the promoter of Bmp4 and Dcn in vivo in a RA-dependent fashion [39].
• Bmp4 heterozygous males on a largely C57BL/6 background show compromised fertility due to degeneration of germ cells, reduced sperm counts, and decreased sperm motility [40].
• Local application of bone morphogenetic protein 4 (BMP4) in the epithelium of molar territories either by bead implantation or by electroporation stimulated Islet1 expression [17].

References