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Gene Review

Wdr5  -  WD repeat domain 5

Mus musculus

Synonyms: 2410008O07Rik, AA408785, AA960360, BMP2-induced 3-kb gene protein, Big, ...
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Disease relevance of Wdr5

  • METHODS: Big Blue transgenic male mice (C57Bl/6) were inoculated with H. pylori (strain SS1) or Helicobacter felis (strain CS1) for 6 and 12 months [1].
  • The incidence of MNU-induced lymphomas was 84% in Big Blue lacI mice compared to 14% in MGMT+Big Blue lacI mice [2].
  • The animals were killed 16 weeks after operation or injection, the entire esophageal mucosa was harvested, and mutation frequency was determined through standard Big Blue Mutagenesis Assay. RESULTS: Gross esophagitis was evident in all operated animals [3].
  • The Big Blue transgenic B6C3F1 mouse carries multiple copies of bacteriophage lambda, each with a lacI mutational target gene, integrated into mouse chromosome 4 [4].
  • Herein, we present the first analysis of mutation frequency and pattern in thymic tumors from a mouse model of Li-Fraumeni syndrome (p53+/- murine model) using the Big Blue assay with sequencing of all mutants [5].

Psychiatry related information on Wdr5

  • No changes in locomotor activity and no signs of anxiolytic-like behavior were produced by dynorphins A and B. Big Dyn (2.5 nmol) increased time spent in the open branches of the elevated plus maze apparatus with no changes in general locomotion [6].

High impact information on Wdr5


Chemical compound and disease context of Wdr5

  • When Big Blue(trade mark) mice were treated with MMS (160 mg/kg) or ENU (125 or 250 mg/kg) and the phages rescued from mature sperm were infected to the strains, the mutation frequency (MF) of phages from ENU-treated mice at a dose of 250 mg/kg in strain YG5152 was about two times higher than that in strain SCS-8 [11].
  • Evaluation of the genetic toxicity of the peroxisome proliferator and carcinogen methyl clofenapate, including assays using Muta Mouse and Big Blue transgenic mice [12].
  • METHODS: Big Blue mouse embryonic fibroblasts, which carry a lambda phage cII transgene, were treated with acrylamide [13].

Biological context of Wdr5


Anatomical context of Wdr5

  • Overall, our findings suggest that Wdr5 accelerates osteoblast differentiation in association with activation of the canonical Wnt pathway [14].
  • Using differential display polymerase chain reaction, we have identified a novel gene, named BIG-3 (BMP-2-induced gene 3 kb), that is induced as a murine prechondroblastic cell line, MLB13MYC clone 17, acquires osteoblastic features in response to BMP-2 treatment [19].
  • We investigated the effects of single and combined exposures to two ubiquitous environmental carcinogens, polycyclic aromatic hydrocarbons and UVA radiation, in Big Blue mouse embryonic fibroblasts [20].
  • To this end, a study was conducted to determine the Mfs and spectrum of mutations induced at these loci in splenic T cells from male B6C3F1 Big Blue mice (6 weeks old) exposed to N-ethyl-N-nitrosourea (ENU) [21].
  • Treatment of the E15 or the P1 SCG with BMP-2 induced expression of trkC mRNA and responsiveness of sympathetic neurons to NT3 as measured by neurite outgrowth [22].

Associations of Wdr5 with chemical compounds


Physical interactions of Wdr5

  • These results strongly suggest that both the Hox- and the Smad-binding regions play a role in BMP-2-induced activation of the OPN promoter [28].

Regulatory relationships of Wdr5

  • The enforced expression of Cdk6 blocked BMP-2-induced osteoblast differentiation to various degrees, depending on the level of its overexpression [15].
  • Over-expression of Wnt3a blocked BMP-2-induced inhibition of myotube formation in C2C12 cells when switched to low mitogen medium [29].
  • Specific inhibitors for p38 kinase inhibited BMP2-induced adipocytic differentiation and transcriptional activation of PPARgamma, whereas overexpression of Smad6 had no effect on transcriptional activity of PPARgamma [30].
  • Expression of dominant-negative PI 3-kinase or dominant-negative Akt inhibited BMP-2-induced BMP-2 transcription [31].
  • These data show that SKIP has specific inhibitory effects on BMP-2-induced differentiation and implicate SKIP to be a novel regulator of the differentiation programming induced by TGF-beta signals [32].

Other interactions of Wdr5


Analytical, diagnostic and therapeutic context of Wdr5

  • In addition, intraarticular injections of BMP-2 induced chondrophytes [38].
  • Real-time quantitative RT-PCR analysis was used to validate BMP2-induced gene expression patterns in C2C12 cells [39].
  • Our studies were designed to determine whether the Big Blue system could be used to detect differences in the in vivo mutagenic activity between the carcinogen/non-carcinogen pair 2,4- and 2,6-DAT and to determine whether the in vivo mutagenesis assay results correspond to the rodent carcinogen bioassay results [4].
  • In this study, the DNA sequence spectra of lacI mutations observed in the liver of B[a]P-treated Big Blue mice at hepatectomy and at time of sacrifice were compared with each other and with the spectrum of spontaneous liver mutations [40].
  • Whereas dynorphins A and B (i.c.v., 0.05 and 7 nmol/animal, respectively) produced analgesia in the hot-plate test Big Dyn did not [6].


  1. Chronic Helicobacter pylori infections induce gastric mutations in mice. Touati, E., Michel, V., Thiberge, J.M., Wuscher, N., Huerre, M., Labigne, A. Gastroenterology (2003) [Pubmed]
  2. Mice over-expressing human O6 alkylguanine-DNA alkyltransferase selectively reduce O6 methylguanine mediated carcinogenic mutations to threshold levels after N-methyl-N-nitrosourea. Allay, E., Veigl, M., Gerson, S.L. Oncogene (1999) [Pubmed]
  3. The mutagenic potential of duodenoesophageal reflux. Theisen, J., Peters, J.H., Fein, M., Hughes, M., Hagen, J.A., Demeester, S.R., Demeester, T.R., Laird, P.W. Ann. Surg. (2005) [Pubmed]
  4. Differential in vivo mutagenicity of the carcinogen/non-carcinogen pair 2,4- and 2,6-diaminotoluene. Hayward, J.J., Shane, B.S., Tindall, K.R., Cunningham, M.L. Carcinogenesis (1995) [Pubmed]
  5. Most spontaneous tumors in a mouse model of Li-Fraumeni syndrome do not have a mutator phenotype. Hill, K.A., Buettner, V.L., Heidt, A., Chen, L.L., Li, W., Gonzalez, K.D., Wang, J.C., Scaringe, W.A., Sommer, S.S. Carcinogenesis (2006) [Pubmed]
  6. Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolytic-like and locomotor behavior in mice. Kuzmin, A., Madjid, N., Terenius, L., Ogren, S.O., Bakalkin, G. Neuropsychopharmacology (2006) [Pubmed]
  7. Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Yoshida, Y., Tanaka, S., Umemori, H., Minowa, O., Usui, M., Ikematsu, N., Hosoda, E., Imamura, T., Kuno, J., Yamashita, T., Miyazono, K., Noda, M., Noda, T., Yamamoto, T. Cell (2000) [Pubmed]
  8. The nucleocytoplasmic shuttling protein CIZ reduces adult bone mass by inhibiting bone morphogenetic protein-induced bone formation. Morinobu, M., Nakamoto, T., Hino, K., Tsuji, K., Shen, Z.J., Nakashima, K., Nifuji, A., Yamamoto, H., Hirai, H., Noda, M. J. Exp. Med. (2005) [Pubmed]
  9. Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation. Zhao, M., Harris, S.E., Horn, D., Geng, Z., Nishimura, R., Mundy, G.R., Chen, D. J. Cell Biol. (2002) [Pubmed]
  10. Differential roles for bone morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. Chen, D., Ji, X., Harris, M.A., Feng, J.Q., Karsenty, G., Celeste, A.J., Rosen, V., Mundy, G.R., Harris, S.E. J. Cell Biol. (1998) [Pubmed]
  11. Effects of O (6)-alkylguanine-DNA alkyltransferase deficiency in Escherichia coli as the host for the detection of mutations in lacI transgenic mice. Sui, H., Suzuki, M., Yamada, M., Hara, T., Kawakami, K., Shibuya, T., Nohmi, T., Sofuni, T. Environ. Mol. Mutagen. (1999) [Pubmed]
  12. Evaluation of the genetic toxicity of the peroxisome proliferator and carcinogen methyl clofenapate, including assays using Muta Mouse and Big Blue transgenic mice. Lefevre, P.A., Tinwell, H., Galloway, S.M., Hill, R., Mackay, J.M., Elcombe, C.R., Foster, J., Randall, V., Callander, R.D., Ashby, J. Human & experimental toxicology. (1994) [Pubmed]
  13. Weak yet distinct mutagenicity of acrylamide in mammalian cells. Besaratinia, A., Pfeifer, G.P. J. Natl. Cancer Inst. (2003) [Pubmed]
  14. Wdr5, a WD-40 protein, regulates osteoblast differentiation during embryonic bone development. Gori, F., Friedman, L.G., Demay, M.B. Dev. Biol. (2006) [Pubmed]
  15. Bone morphogenetic protein 2-induced osteoblast differentiation requires Smad-mediated down-regulation of Cdk6. Ogasawara, T., Kawaguchi, H., Jinno, S., Hoshi, K., Itaka, K., Takato, T., Nakamura, K., Okayama, H. Mol. Cell. Biol. (2004) [Pubmed]
  16. Damage, repair, and mutagenesis in nuclear genes after mouse forebrain ischemia-reperfusion. Liu, P.K., Hsu, C.Y., Dizdaroglu, M., Floyd, R.A., Kow, Y.W., Karakaya, A., Rabow, L.E., Cui, J.K. J. Neurosci. (1996) [Pubmed]
  17. Protein kinase C-independent activation of protein kinase D is involved in BMP-2-induced activation of stress mitogen-activated protein kinases JNK and p38 and osteoblastic cell differentiation. Lemonnier, J., Ghayor, C., Guicheux, J., Caverzasio, J. J. Biol. Chem. (2004) [Pubmed]
  18. Negative regulation of bone morphogenetic protein/Smad signaling by Cas-interacting zinc finger protein in osteoblasts. Shen, Z.J., Nakamoto, T., Tsuji, K., Nifuji, A., Miyazono, K., Komori, T., Hirai, H., Noda, M. J. Biol. Chem. (2002) [Pubmed]
  19. Cloning and characterization of a novel WD-40 repeat protein that dramatically accelerates osteoblastic differentiation. Gori, F., Divieti, P., Demay, M.B. J. Biol. Chem. (2001) [Pubmed]
  20. Enhancement of the mutagenicity of benzo(a)pyrene diol epoxide by a nonmutagenic dose of ultraviolet A radiation. Besaratinia, A., Pfeifer, G.P. Cancer Res. (2003) [Pubmed]
  21. Frequency and spectrum of ethylnitrosourea-induced mutation at the hprt and lacI loci in splenic lymphocytes of exposed lacI transgenic mice. Walker, V.E., Gorelick, N.J., Andrews, J.L., Craft, T.R., deBoer, J.G., Glickman, B.W., Skopek, T.R. Cancer Res. (1996) [Pubmed]
  22. Development of bone morphogenetic protein receptors in the nervous system and possible roles in regulating trkC expression. Zhang, D., Mehler, M.F., Song, Q., Kessler, J.A. J. Neurosci. (1998) [Pubmed]
  23. Induction of osteoblast differentiation by selective activation of kinase-mediated actions of the estrogen receptor. Kousteni, S., Almeida, M., Han, L., Bellido, T., Jilka, R.L., Manolagas, S.C. Mol. Cell. Biol. (2007) [Pubmed]
  24. Mutational signature of the proximate bladder carcinogen N-hydroxy-4-acetylaminobiphenyl: inconsistency with the p53 mutational spectrum in bladder cancer. Besaratinia, A., Bates, S.E., Pfeifer, G.P. Cancer Res. (2002) [Pubmed]
  25. Bone morphogenetic protein 2 induces cyclo-oxygenase 2 in osteoblasts via a Cbfal binding site: role in effects of bone morphogenetic protein 2 in vitro and in vivo. Chikazu, D., Li, X., Kawaguchi, H., Sakuma, Y., Voznesensky, O.S., Adams, D.J., Xu, M., Hoshio, K., Katavic, V., Herschman, H.R., Raisz, L.G., Pilbeam, C.C. J. Bone Miner. Res. (2002) [Pubmed]
  26. Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation. Guicheux, J., Lemonnier, J., Ghayor, C., Suzuki, A., Palmer, G., Caverzasio, J. J. Bone Miner. Res. (2003) [Pubmed]
  27. Oxazepam is mutagenic in vivo in Big Blue transgenic mice. Shane, B.S., deBoer, J.G., Glickman, B.W., Cunningham, M.L. Carcinogenesis (1999) [Pubmed]
  28. TGFbeta and BMP-2 activation of the OPN promoter: roles of smad- and hox-binding elements. Hullinger, T.G., Pan, Q., Viswanathan, H.L., Somerman, M.J. Exp. Cell Res. (2001) [Pubmed]
  29. Cross-talk between Wnt and bone morphogenetic protein 2 (BMP-2) signaling in differentiation pathway of C2C12 myoblasts. Nakashima, A., Katagiri, T., Tamura, M. J. Biol. Chem. (2005) [Pubmed]
  30. Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor gamma during bone morphogenetic protein 2-induced adipogenesis. Hata, K., Nishimura, R., Ikeda, F., Yamashita, K., Matsubara, T., Nokubi, T., Yoneda, T. Mol. Biol. Cell (2003) [Pubmed]
  31. Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription. Ghosh-Choudhury, N., Abboud, S.L., Nishimura, R., Celeste, A., Mahimainathan, L., Choudhury, G.G. J. Biol. Chem. (2002) [Pubmed]
  32. Differential effects of the Ski-interacting protein (SKIP) on differentiation induced by transforming growth factor-beta1 and bone morphogenetic protein-2 in C2C12 cells. Figueroa, J.D., Hayman, M.J. Exp. Cell Res. (2004) [Pubmed]
  33. BMP-2-induced Runx2 expression is mediated by Dlx5, and TGF-beta 1 opposes the BMP-2-induced osteoblast differentiation by suppression of Dlx5 expression. Lee, M.H., Kim, Y.J., Kim, H.J., Park, H.D., Kang, A.R., Kyung, H.M., Sung, J.H., Wozney, J.M., Kim, H.J., Ryoo, H.M. J. Biol. Chem. (2003) [Pubmed]
  34. Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling. Nobta, M., Tsukazaki, T., Shibata, Y., Xin, C., Moriishi, T., Sakano, S., Shindo, H., Yamaguchi, A. J. Biol. Chem. (2005) [Pubmed]
  35. Involvement of ERK in BMP-2 induced osteoblastic differentiation of mesenchymal progenitor cell line C3H10T1/2. Lou, J., Tu, Y., Li, S., Manske, P.R. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  36. Bone morphogenetic protein-2 (BMP-2) transactivates Dlx3 through Smad1 and Smad4: alternative mode for Dlx3 induction in mouse keratinocytes. Park, G.T., Morasso, M.I. Nucleic Acids Res. (2002) [Pubmed]
  37. BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. Kimura, N., Matsuo, R., Shibuya, H., Nakashima, K., Taga, T. J. Biol. Chem. (2000) [Pubmed]
  38. Bone morphogenetic protein 2 stimulates articular cartilage proteoglycan synthesis in vivo but does not counteract interleukin-1alpha effects on proteoglycan synthesis and content. Glansbeek, H.L., van Beuningen, H.M., Vitters, E.L., Morris, E.A., van der Kraan, P.M., van den Berg, W.B. Arthritis Rheum. (1997) [Pubmed]
  39. Identification of novel regulators associated with early-phase osteoblast differentiation. de Jong, D.S., Vaes, B.L., Dechering, K.J., Feijen, A., Hendriks, J.M., Wehrens, R., Mummery, C.L., van Zoelen, E.J., Olijve, W., Steegenga, W.T. J. Bone Miner. Res. (2004) [Pubmed]
  40. LacI mutation spectra following benzo[a]pyrene treatment of Big Blue mice. Shane, B.S., de Boer, J., Watson, D.E., Haseman, J.K., Glickman, B.W., Tindall, K.R. Carcinogenesis (2000) [Pubmed]
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