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Gene Review

Msx2  -  msh homeobox 2

Mus musculus

Synonyms: BB122635, Homeobox protein Hox-8-1, Homeobox protein MSX-2, Hox-8, Hox-8.1, ...
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Disease relevance of Msx2

  • A ternary complex of necdin, MAGE-D1, and Msx2 was formed in vitro, and an endogenous complex containing these three proteins was detected in differentiating embryonal carcinoma cells [1].
  • We provide evidence that targeted infection in ovo using adenovirus containing Msx2 and a reporter molecule indicative of translation can induce apoptosis in either even- or odd-numbered rhombomeres [2].
  • We provide evidence indicating that the lack of interdigital cell death and associated syndactyly is related to an absence of interdigital cells marked by expression of Fgfr2 and Msx2 [3].
  • In addition, cotransfection studies in ROS 17/2.8 osteosarcoma cells using an Msx2 expression vector showed that Msx2 inhibits a COL1A1 promoter-chloramphenicol acetyltransferase construct [4].
  • In the second, a mouse model of the human disease craniosynostosis, Boston type, has been created by misregulation of the Msx2 gene product [5].

High impact information on Msx2

  • Most Msx2-mutant phenotypes, including calvarial defects, are enhanced by genetic combination with Msx1 loss of function, indicating that Msx gene dosage can modify expression of the PFM phenotype [6].
  • Consistent with phenotypes associated with PFM, Msx2-mutant mice also display defective tooth, hair follicle and mammary gland development, and seizures, the latter accompanied by abnormal development of the cerebellum [6].
  • Msx2-/- mice also have defects in endochondral bone formation [6].
  • Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation [6].
  • Our results provide a developmental basis for PFM and demonstrate that Msx2 is essential at multiple sites during organogenesis [6].

Chemical compound and disease context of Msx2

  • We demonstrated previously that individuals affected with an autosomal dominant disorder of skull morphogenesis (craniosynostosis, Boston type) bear a mutated form of Msx2 in which a histidine is substituted for a highly conserved proline in position 7 of the N-terminal arm of the homeodomain (p148h) [7].

Biological context of Msx2


Anatomical context of Msx2


Associations of Msx2 with chemical compounds

  • Of the three sutures studied, the coronal suture exhibited the greatest increase in Msx2 expression and was the most likely to undergo obliteration and fusion [14].
  • The effect of Msx2 overexpression on retinal cell proliferation was assayed by bromodeoxyuridine (BrdU) incorporation and immunohistochemical staining [11].
  • Regardless of cholesterol content, high fat diets induced mineralization of the proximal aorta (assessed by von Kossa staining) and promoted aortic expression of Msx2 and Msx1, genes encoding homeodomain transcription factors that regulate mineralization and osseous differentiation programs in the developing skull [15].
  • By contrast, GST-Msx2 has no effect on calcitriol-regulated DNA-protein interactions at the VDRE [16].
  • Finally, Msx2-/- uteri were found to exhibit abnormal water trafficking upon DES exposure, demonstrating the importance of Msx2 in tissue responsiveness to estrogen exposure [17].

Physical interactions of Msx2


Regulatory relationships of Msx2


Other interactions of Msx2

  • These results are consistent with functional redundancy between Msx1 and Msx2 in dental mesenchyme and support a model whereby Msx and Dlx genes function in parallel within the dental mesenchyme during tooth initiation [24].
  • To better understand Msx2 regulation of the OCFRE, we have studied functional interactions between MINT and Runx2, a master regulator of osteoblast differentiation [9].
  • Msx2 expression continued in the epithelial cell rests of Malassez, and the nearby cementoblasts intensely expressed Bmp3, which may regulate some functions of the fragmented epithelium [21].
  • BMP-2 treatment completely blocked myotube formation and transiently induced expression of Cbfa1 and the bone-related homeodomain protein Msx-2 concomitant with loss of the myoblast phenotype [25].
  • In this study, we have localized the ossification defect in ch mutants to the calvarial mesenchyme, which lacks the expression of transcription factors Msx2 and Alx4 [26].

Analytical, diagnostic and therapeutic context of Msx2

  • In both fetal and neonatal digits, we find that both Msx1 and Msx2 are expressed during regeneration, but not during wound healing associated with proximal amputations where no regenerative response is observed [27].
  • We show that Msx2, a homeodomain protein, binds to this motif; however, Northern blot analysis revealed that Msx2 mRNA is present in undifferentiated bone cells but not in fully differentiated osteoblasts [4].
  • Protein-protein interaction between Msx2 and C/EBPalpha is identified with co-immunoprecipitation analyses [20].
  • Electrophoresis mobility shift assays demonstrate that Msx2 interferes with the binding of C/EBPalpha to its cognate site in the mouse amelogenin minimal promoter, although Msx2 itself does not bind to the same promoter fragment [20].
  • Western blot analysis of fractionated cell extracts reveals that mature approximately 110 kDa (N-terminal) and approximately 250 kDa (C-terminal) MINT protein fragments accumulate in chromatin and nuclear matrix fractions, cosegregating with Msx2 and topoisomerase II [28].


  1. Necdin interacts with the Msx2 homeodomain protein via MAGE-D1 to promote myogenic differentiation of C2C12 cells. Kuwajima, T., Taniura, H., Nishimura, I., Yoshikawa, K. J. Biol. Chem. (2004) [Pubmed]
  2. Adenovirus-mediated ectopic expression of Msx2 in even-numbered rhombomeres induces apoptotic elimination of cranial neural crest cells in ovo. Takahashi, K., Nuckolls, G.H., Tanaka, O., Semba, I., Takahashi, I., Dashner, R., Shum, L., Slavkin, H.C. Development (1998) [Pubmed]
  3. Activities of N-Myc in the developing limb link control of skeletal size with digit separation. Ota, S., Zhou, Z.Q., Keene, D.R., Knoepfler, P., Hurlin, P.J. Development (2007) [Pubmed]
  4. Identification of a TAAT-containing motif required for high level expression of the COL1A1 promoter in differentiated osteoblasts of transgenic mice. Dodig, M., Kronenberg, M.S., Bedalov, A., Kream, B.E., Gronowicz, G., Clark, S.H., Mack, K., Liu, Y.H., Maxon, R., Pan, Z.Z., Upholt, W.B., Rowe, D.W., Lichtler, A.C. J. Biol. Chem. (1996) [Pubmed]
  5. Genetically engineered mice: tools to understand craniofacial development. Ignelzi, M.A., Liu, Y.H., Maxson, R.E., Snead, M.L. Crit. Rev. Oral Biol. Med. (1995) [Pubmed]
  6. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Satokata, I., Ma, L., Ohshima, H., Bei, M., Woo, I., Nishizawa, K., Maeda, T., Takano, Y., Uchiyama, M., Heaney, S., Peters, H., Tang, Z., Maxson, R., Maas, R. Nat. Genet. (2000) [Pubmed]
  7. Miz1, a novel zinc finger transcription factor that interacts with Msx2 and enhances its affinity for DNA. Wu, L., Wu, H., Ma, L., Sangiorgi, F., Wu, N., Bell, J.R., Lyons, G.E., Maxson, R. Mech. Dev. (1997) [Pubmed]
  8. MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors. Cheng, S.L., Shao, J.S., Charlton-Kachigian, N., Loewy, A.P., Towler, D.A. J. Biol. Chem. (2003) [Pubmed]
  9. MINT, the Msx2 interacting nuclear matrix target, enhances Runx2-dependent activation of the osteocalcin fibroblast growth factor response element. Sierra, O.L., Cheng, S.L., Loewy, A.P., Charlton-Kachigian, N., Towler, D.A. J. Biol. Chem. (2004) [Pubmed]
  10. In vivo evidence that BMP signaling is necessary for apoptosis in the mouse limb. Guha, U., Gomes, W.A., Kobayashi, T., Pestell, R.G., Kessler, J.A. Dev. Biol. (2002) [Pubmed]
  11. Microphthalmia resulting from MSX2-induced apoptosis in the optic vesicle. Wu, L.Y., Li, M., Hinton, D.R., Guo, L., Jiang, S., Wang, J.T., Zeng, A., Xie, J.B., Snead, M., Shuler, C., Maxson, R.E., Liu, Y.H. Invest. Ophthalmol. Vis. Sci. (2003) [Pubmed]
  12. Homeobox protein MSX2 acts as a molecular defense mechanism for preventing ossification in ligament fibroblasts. Yoshizawa, T., Takizawa, F., Iizawa, F., Ishibashi, O., Kawashima, H., Matsuda, A., Endo, N., Kawashima, H. Mol. Cell. Biol. (2004) [Pubmed]
  13. FGF-, BMP- and Shh-mediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. Kim, H.J., Rice, D.P., Kettunen, P.J., Thesleff, I. Development (1998) [Pubmed]
  14. Fibroblast growth factors lead to increased Msx2 expression and fusion in calvarial sutures. Ignelzi, M.A., Wang, W., Young, A.T. J. Bone Miner. Res. (2003) [Pubmed]
  15. Diet-induced diabetes activates an osteogenic gene regulatory program in the aortas of low density lipoprotein receptor-deficient mice. Towler, D.A., Bidder, M., Latifi, T., Coleman, T., Semenkovich, C.F. J. Biol. Chem. (1998) [Pubmed]
  16. Stimulus-selective inhibition of rat osteocalcin promoter induction and protein-DNA interactions by the homeodomain repressor Msx2. Newberry, E.P., Boudreaux, J.M., Towler, D.A. J. Biol. Chem. (1997) [Pubmed]
  17. Developmental diethylstilbestrol exposure alters genetic pathways of uterine cytodifferentiation. Huang, W.W., Yin, Y., Bi, Q., Chiang, T.C., Garner, N., Vuoristo, J., McLachlan, J.A., Ma, L. Mol. Endocrinol. (2005) [Pubmed]
  18. YY1 activates Msx2 gene independent of bone morphogenetic protein signaling. Tan, D.P., Nonaka, K., Nuckolls, G.H., Liu, Y.H., Maxson, R.E., Slavkin, H.C., Shum, L. Nucleic Acids Res. (2002) [Pubmed]
  19. MSX2 expression in the apical ectoderm ridge is regulated by an MSX2 and Dlx5 binding site. Pan, Z.Z., Kronenberg, M.S., Huang, D.Y., Sumoy, L., Rogina, B., Lichtler, A.C., Upholt, W.B. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  20. Functional antagonism between Msx2 and CCAAT/enhancer-binding protein alpha in regulating the mouse amelogenin gene expression is mediated by protein-protein interaction. Zhou, Y.L., Lei, Y., Snead, M.L. J. Biol. Chem. (2000) [Pubmed]
  21. Expression of bone morphogenetic proteins and Msx genes during root formation. Yamashiro, T., Tummers, M., Thesleff, I. J. Dent. Res. (2003) [Pubmed]
  22. Reciprocal roles of MSX2 in regulation of osteoblast and adipocyte differentiation. Ichida, F., Nishimura, R., Hata, K., Matsubara, T., Ikeda, F., Hisada, K., Yatani, H., Cao, X., Komori, T., Yamaguchi, A., Yoneda, T. J. Biol. Chem. (2004) [Pubmed]
  23. Smad4 and beta-catenin co-activators functionally interact with lymphoid-enhancing factor to regulate graded expression of Msx2. Hussein, S.M., Duff, E.K., Sirard, C. J. Biol. Chem. (2003) [Pubmed]
  24. FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development. Bei, M., Maas, R. Development (1998) [Pubmed]
  25. Transient upregulation of CBFA1 in response to bone morphogenetic protein-2 and transforming growth factor beta1 in C2C12 myogenic cells coincides with suppression of the myogenic phenotype but is not sufficient for osteoblast differentiation. Lee, M.H., Javed, A., Kim, H.J., Shin, H.I., Gutierrez, S., Choi, J.Y., Rosen, V., Stein, J.L., van Wijnen, A.J., Stein, G.S., Lian, J.B., Ryoo, H.M. J. Cell. Biochem. (1999) [Pubmed]
  26. Progression of calvarial bone development requires Foxc1 regulation of Msx2 and Alx4. Rice, R., Rice, D.P., Olsen, B.R., Thesleff, I. Dev. Biol. (2003) [Pubmed]
  27. Digit tip regeneration correlates with regions of Msx1 (Hox 7) expression in fetal and newborn mice. Reginelli, A.D., Wang, Y.Q., Sassoon, D., Muneoka, K. Development (1995) [Pubmed]
  28. The RRM domain of MINT, a novel Msx2 binding protein, recognizes and regulates the rat osteocalcin promoter. Newberry, E.P., Latifi, T., Towler, D.A. Biochemistry (1999) [Pubmed]
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