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Gene Review

Bmp4  -  bone morphogenetic protein 4

Mus musculus

Synonyms: BMP-2B, BMP-4, Bmp-4, Bmp2b, Bmp2b-1, ...
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Disease relevance of Bmp4


High impact information on Bmp4


Chemical compound and disease context of Bmp4


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


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


  1. 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. Nakase, T., Ariga, K., Miyamoto, S., Okuda, S., Tomita, T., Iwasaki, M., Yonenobu, K., Yoshikawa, H. J. Neurosurg. (2001) [Pubmed]
  2. Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. Okamoto, M., Murai, J., Yoshikawa, H., Tsumaki, N. J. Bone Miner. Res. (2006) [Pubmed]
  3. Hypoxia affects mesoderm and enhances hemangioblast specification during early development. Ramírez-Bergeron, D.L., Runge, A., Dahl, K.D., Fehling, H.J., Keller, G., Simon, M.C. Development (2004) [Pubmed]
  4. Target-derived BMP signaling limits sensory neuron number and the extent of peripheral innervation in vivo. Guha, U., Gomes, W.A., Samanta, J., Gupta, M., Rice, F.L., Kessler, J.A. Development (2004) [Pubmed]
  5. Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype. Kan, L., Hu, M., Gomes, W.A., Kessler, J.A. Am. J. Pathol. (2004) [Pubmed]
  6. BMP4, SCF, and hypoxia cooperatively regulate the expansion of murine stress erythroid progenitors. Perry, J.M., Harandi, O.F., Paulson, R.F. Blood (2007) [Pubmed]
  7. Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4. Piccolo, S., Sasai, Y., Lu, B., De Robertis, E.M. Cell (1996) [Pubmed]
  8. Identification of BMP-4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development. Vainio, S., Karavanova, I., Jowett, A., Thesleff, I. Cell (1993) [Pubmed]
  9. Function of Rieger syndrome gene in left-right asymmetry and craniofacial development. Lu, M.F., Pressman, C., Dyer, R., Johnson, R.L., Martin, J.F. Nature (1999) [Pubmed]
  10. BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. de Sousa Lopes, S.M., Roelen, B.A., Monteiro, R.M., Emmens, R., Lin, H.Y., Li, E., Lawson, K.A., Mummery, C.L. Genes Dev. (2004) [Pubmed]
  11. BMP-4 and retinoic acid synergistically induce activation of caspase-9 and cause apoptosis of P19 embryonal carcinoma cells cultured as a monolayer. Fujita, E., Soyama, A., Kawabata, M., Momoi, T. Cell Death Differ. (1999) [Pubmed]
  12. Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter. Miyazaki, Y., Oshima, K., Fogo, A., Hogan, B.L., Ichikawa, I. J. Clin. Invest. (2000) [Pubmed]
  13. Conservation of early odontogenic signaling pathways in Aves. Chen, Y., Zhang, Y., Jiang, T.X., Barlow, A.J., St Amand, T.R., Hu, Y., Heaney, S., Francis-West, P., Chuong, C.M., Maas, R. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  14. The docking protein FRS2alpha is an essential component of multiple fibroblast growth factor responses during early mouse development. Gotoh, N., Manova, K., Tanaka, S., Murohashi, M., Hadari, Y., Lee, A., Hamada, Y., Hiroe, T., Ito, M., Kurihara, T., Nakazato, H., Shibuya, M., Lax, I., Lacy, E., Schlessinger, J. Mol. Cell. Biol. (2005) [Pubmed]
  15. Unique functions of Sonic hedgehog signaling during external genitalia development. Haraguchi, R., Mo, R., Hui, C., Motoyama, J., Makino, S., Shiroishi, T., Gaffield, W., Yamada, G. Development (2001) [Pubmed]
  16. BMP4 is essential for lens induction in the mouse embryo. Furuta, Y., Hogan, B.L. Genes Dev. (1998) [Pubmed]
  17. Role of Islet1 in the patterning of murine dentition. Mitsiadis, T.A., Angeli, I., James, C., Lendahl, U., Sharpe, P.T. Development (2003) [Pubmed]
  18. Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Naski, M.C., Colvin, J.S., Coffin, J.D., Ornitz, D.M. Development (1998) [Pubmed]
  19. Essential pro-Bmp roles of crossveinless 2 in mouse organogenesis. Ikeya, M., Kawada, M., Kiyonari, H., Sasai, N., Nakao, K., Furuta, Y., Sasai, Y. Development (2006) [Pubmed]
  20. Gli3 is required for Emx gene expression during dorsal telencephalon development. Theil, T., Alvarez-Bolado, G., Walter, A., Rüther, U. Development (1999) [Pubmed]
  21. Molecular regulation of urothelial renewal and host defenses during infection with uropathogenic Escherichia coli. Mysorekar, I.U., Mulvey, M.A., Hultgren, S.J., Gordon, J.I. J. Biol. Chem. (2002) [Pubmed]
  22. Bone morphogenetic protein 4 is involved in cusp formation in molar tooth germ of mice. Tabata, M.J., Fujii, T., Liu, J.G., Ohmori, T., Abe, M., Wakisaka, S., Iwamoto, M., Kurisu, K. Eur. J. Oral Sci. (2002) [Pubmed]
  23. Bone morphogenetic protein regulation of forkhead/winged helix transcription factor Foxc2 (Mfh1) in a murine mesodermal cell line C1 and in skeletal precursor cells. Nifuji, A., Miura, N., Kato, N., Kellermann, O., Noda, M. J. Bone Miner. Res. (2001) [Pubmed]
  24. BMP action in skeletogenesis involves attenuation of retinoid signaling. Hoffman, L.M., Garcha, K., Karamboulas, K., Cowan, M.F., Drysdale, L.M., Horton, W.A., Underhill, T.M. J. Cell Biol. (2006) [Pubmed]
  25. Retinoic acid repression of bone morphogenetic protein 4 in inner ear development. Thompson, D.L., Gerlach-Bank, L.M., Barald, K.F., Koenig, R.J. Mol. Cell. Biol. (2003) [Pubmed]
  26. Interaction between soluble type I receptor for bone morphogenetic protein and bone morphogenetic protein-4. Natsume, T., Tomita, S., Iemura, S., Kinto, N., Yamaguchi, A., Ueno, N. J. Biol. Chem. (1997) [Pubmed]
  27. Transcription factor CP2 is involved in activating mBMP4 in mouse mesenchymal stem cells. Kang, H.C., Chae, J.H., Kim, B.S., Han, S.Y., Kim, S.H., Auh, C.K., Yang, S.I., Kim, C.G. Mol. Cells (2004) [Pubmed]
  28. SMAD1 signaling is critical for initial commitment of germ cell lineage from mouse epiblast. Hayashi, K., Kobayashi, T., Umino, T., Goitsuka, R., Matsui, Y., Kitamura, D. Mech. Dev. (2002) [Pubmed]
  29. Involvement of p70 S6 kinase in bone morphogenetic protein signaling: vascular endothelial growth factor synthesis by bone morphogenetic protein-4 in osteoblasts. Kozawa, O., Matsuno, H., Uematsu, T. J. Cell. Biochem. (2001) [Pubmed]
  30. FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development. Bei, M., Maas, R. Development (1998) [Pubmed]
  31. Transgenically ectopic expression of Bmp4 to the Msx1 mutant dental mesenchyme restores downstream gene expression but represses Shh and Bmp2 in the enamel knot of wild type tooth germ. Zhao, X., Zhang, Z., Song, Y., Zhang, X., Zhang, Y., Hu, Y., Fromm, S.H., Chen, Y. Mech. Dev. (2000) [Pubmed]
  32. Expression of bone morphogenetic proteins and Msx genes during root formation. Yamashiro, T., Tummers, M., Thesleff, I. J. Dent. Res. (2003) [Pubmed]
  33. BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb. Ahn, K., Mishina, Y., Hanks, M.C., Behringer, R.R., Crenshaw, E.B. Development (2001) [Pubmed]
  34. Formation of Rathke's pouch requires dual induction from the diencephalon. Takuma, N., Sheng, H.Z., Furuta, Y., Ward, J.M., Sharma, K., Hogan, B.L., Pfaff, S.L., Westphal, H., Kimura, S., Mahon, K.A. Development (1998) [Pubmed]
  35. Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis. Weaver, M., Dunn, N.R., Hogan, B.L. Development (2000) [Pubmed]
  36. Sonic hedgehog signaling is essential for hair development. St-Jacques, B., Dassule, H.R., Karavanova, I., Botchkarev, V.A., Li, J., Danielian, P.S., McMahon, J.A., Lewis, P.M., Paus, R., McMahon, A.P. Curr. Biol. (1998) [Pubmed]
  37. Evidence that bone morphogenetic protein 4 has multiple biological functions during kidney and urinary tract development. Miyazaki, Y., Oshima, K., Fogo, A., Ichikawa, I. Kidney Int. (2003) [Pubmed]
  38. Signaling to the epithelium is not sufficient to mediate all of the effects of transforming growth factor beta and bone morphogenetic protein 4 on murine embryonic lung development. Bragg, A.D., Moses, H.L., Serra, R. Mech. Dev. (2001) [Pubmed]
  39. Pre-B cell leukemia transcription factor (PBX) proteins are important mediators for retinoic acid-dependent endodermal and neuronal differentiation of mouse embryonal carcinoma P19 cells. Qin, P., Haberbusch, J.M., Zhang, Z., Soprano, K.J., Soprano, D.R. J. Biol. Chem. (2004) [Pubmed]
  40. Developmental expression and function of Bmp4 in spermatogenesis and in maintaining epididymal integrity. Hu, J., Chen, Y.X., Wang, D., Qi, X., Li, T.G., Hao, J., Mishina, Y., Garbers, D.L., Zhao, G.Q. Dev. Biol. (2004) [Pubmed]
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