Msh homeobox 2 explained

Homeobox protein MSX-2 is a protein that in humans is encoded by the MSX2 gene.^{[1] [2] [3]}

Function

This gene encodes a member of the muscle segment homeobox gene family. The encoded protein is a transcriptional repressor whose normal activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis. The encoded protein may also have a role in promoting cell growth under certain conditions and may be an important target for the RAS signaling pathways. Mutations in this gene are associated with parietal foramina 1 and craniosynostosis type 2.^[3] Msx2 is a homeobox gene localized on human chromosome 5 that encodes a transcription repressor and activator (MSX-2) responsible for craniofacial and limb-bud development. Cells will express msx2 when exposed to signaling molecules BMP-2 and BMP-4 in situ.^[4] Expression of msx2 leads to the proliferation, migration and osteogenic differentiation of neural crest cells during embryogenesis and bone fracture.^[5] It is well documented that expression of cell-cell adhesion molecules such as E-cadherins will promote structural integrity and an epithelial arrangement of cells, while expression of N-cadherin and vimentin promote mesenchymal arrangement and cell migration.^{[6] [7]} Msx2 downregulates E-cadherins and upregulates N-cadherin and vimentin which indicates its role in inducing epithelial mesenchymal transition (EMT). Germline knockout mice have been created for this gene (Msx2 +/-) in order to examine functional loss.^[8] Clinical studies on craniosynostosis, or the premature fusion of cranial structures, have shown the condition to be genetically linked to mutation in the msx2 homeobox gene.^[9]

Interactions

Msh homeobox 2 has been shown to interact with DLX5,^[10] DLX2^[10] and MSX1.^[10]

Further reading

• Suzuki M, Tanaka M, Iwase T, Naito Y, Sugimura H, Kino I . Over-expression of HOX-8, the human homologue of the mouse Hox-8 homeobox gene, in human tumors . Biochemical and Biophysical Research Communications . 194 . 1 . 187–93 . July 1993 . 7687426 . 10.1006/bbrc.1993.1802 . 10271/1007 . 27890243 . free .
• Semenza GL, Wang GL, Kundu R . DNA binding and transcriptional properties of wild-type and mutant forms of the homeodomain protein Msx2 . Biochemical and Biophysical Research Communications . 209 . 1 . 257–62 . April 1995 . 7726844 . 10.1006/bbrc.1995.1497 . free .
• Iimura T . [Molecular cloning and expression of homeobox-containing genes during hard tissue development] . Kokubyo Gakkai Zasshi. The Journal of the Stomatological Society, Japan . 61 . 4 . 590–604 . December 1994 . 7897272 . 10.5357/koubyou.61.590 . 2781509 . free .
• Hodgkinson JE, Davidson CL, Beresford J, Sharpe PT . Expression of a human homeobox-containing gene is regulated by 1,25(OH)2D3 in bone cells . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1174 . 1 . 11–6 . July 1993 . 8101453 . 10.1016/0167-4781(93)90086-s .
• Jabs EW, Müller U, Li X, Ma L, Luo W, Haworth IS, Klisak I, Sparkes R, Warman ML, Mulliken JB . A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis . Cell . 75 . 3 . 443–50 . November 1993 . 8106171 . 10.1016/0092-8674(93)90379-5 . 13650758 .
• Ma L, Golden S, Wu L, Maxson R . The molecular basis of Boston-type craniosynostosis: the Pro148→His mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences . Human Molecular Genetics . 5 . 12 . 1915–20 . December 1996 . 8968743 . 10.1093/hmg/5.12.1915 . free .
• Quinn LM, Johnson BV, Nicholl J, Sutherland GR, Kalionis B . Grant Robert Sutherland . Isolation and identification of homeobox genes from the human placenta including a novel member of the Distal-less family, DLX4 . Gene . 187 . 1 . 55–61 . March 1997 . 9073066 . 10.1016/S0378-1119(96)00706-8 .
• Zhang H, Hu G, Wang H, Sciavolino P, Iler N, Shen MM, Abate-Shen C . Heterodimerization of Msx and Dlx homeoproteins results in functional antagonism . Molecular and Cellular Biology . 17 . 5 . 2920–32 . May 1997 . 9111364 . 232144 . 10.1128/mcb.17.5.2920 .
• Wu L, Wu H, Ma L, Sangiorgi F, Wu N, Bell JR, Lyons GE, Maxson R . Miz1, a novel zinc finger transcription factor that interacts with Msx2 and enhances its affinity for DNA . Mechanisms of Development . 65 . 1–2 . 3–17 . July 1997 . 9256341 . 10.1016/S0925-4773(97)00032-4 . 11835268 .
• Newberry EP, Latifi T, Battaile JT, Towler DA . Structure-function analysis of Msx2-mediated transcriptional suppression . Biochemistry . 36 . 34 . 10451–62 . August 1997 . 9265625 . 10.1021/bi971008x .
• Stelnicki EJ, Kömüves LG, Holmes D, Clavin W, Harrison MR, Adzick NS, Largman C . The human homeobox genes MSX-1, MSX-2, and MOX-1 are differentially expressed in the dermis and epidermis in fetal and adult skin . Differentiation; Research in Biological Diversity . 62 . 1 . 33–41 . October 1997 . 9373945 . 10.1046/j.1432-0436.1997.6210033.x . free .
• Iimura T, Takeda K, Goseki M, Maruoka Y, Sasaki S, Oida S . Characterization of two length cDNA for human MSX-2 from dental pulp-derived cells . DNA Sequence . 8 . 1–2 . 87–92 . 1998 . 9522127 . 10.3109/10425179709020891 .
• Newberry EP, Latifi T, Towler DA . The RRM domain of MINT, a novel Msx2 binding protein, recognizes and regulates the rat osteocalcin promoter . Biochemistry . 38 . 33 . 10678–90 . August 1999 . 10451362 . 10.1021/bi990967j .
• Wilkie AO, Tang Z, Elanko N, Walsh S, Twigg SR, Hurst JA, Wall SA, Chrzanowska KH, Maxson RE . Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification . Nature Genetics . 24 . 4 . 387–90 . April 2000 . 10742103 . 10.1038/74224 . 21030594 .
• Wuyts W, Reardon W, Preis S, Homfray T, Rasore-Quartino A, Christians H, Willems PJ, Van Hul W . Identification of mutations in the MSX2 homeobox gene in families affected with foramina parietalia permagna . Human Molecular Genetics . 9 . 8 . 1251–5 . May 2000 . 10767351 . 10.1093/hmg/9.8.1251 . free .
• Quinn LM, Latham SE, Kalionis B . The homeobox genes MSX2 and MOX2 are candidates for regulating epithelial-mesenchymal cell interactions in the human placenta . Placenta . 21 Suppl A . Suppl A . S50-4 . 2000 . 10831122 . 10.1053/plac.1999.0514 .
• Masuda Y, Sasaki A, Shibuya H, Ueno N, Ikeda K, Watanabe K . Dlxin-1, a novel protein that binds Dlx5 and regulates its transcriptional function . The Journal of Biological Chemistry . 276 . 7 . 5331–8 . February 2001 . 11084035 . 10.1074/jbc.M008590200 . free .
• Shirakabe K, Terasawa K, Miyama K, Shibuya H, Nishida E . Regulation of the activity of the transcription factor Runx2 by two homeobox proteins, Msx2 and Dlx5 . Genes to Cells . 6 . 10 . 851–6 . October 2001 . 11683913 . 10.1046/j.1365-2443.2001.00466.x . 22071040 . free .

External links

• GeneReviews/NCBI/UW/NIH entry on Enlarged Parietal Foramina/Cranium Bifidum

Notes and References

1. Takahashi C, Akiyama N, Matsuzaki T, Takai S, Kitayama H, Noda M . Characterization of a human MSX-2 cDNA and its fragment isolated as a transformation suppressor gene against v-Ki-ras oncogene . Oncogene . 12 . 10 . 2137–46 . May 1996 . 8668339 .
2. Kostrzewa M, Grady DL, Moyzis RK, Flöter L, Müller U . Integration of four genes, a pseudogene, thirty-one STSs, and a highly polymorphic STRP into the 7-10 Mb YAC contig of 5q34-q35 . Human Genetics . 97 . 3 . 399–403 . March 1996 . 8786091 . 10.1007/BF02185781 . 12647370 .
3. Web site: Entrez Gene: MSX2 msh homeobox 2.
4. Rifas . L . Gestational exposure to ethanol suppresses msx2 expression in developing mouse embryos. . Proc Natl Acad Sci U S A . July 1997 . 94 . 14 . 7549–54. 1997PNAS...94.7549R . 10.1073/pnas.94.14.7549 . 9207129 . 23859 . free .
5. Liu H, Chen B, Li Y . microRNA-203 promotes proliferation, differentiation, and migration of osteoblasts by upregulation of Msh homeobox 2 . Journal of Cellular Physiology . 234 . 10 . 17639–17648 . March 2019 . 30854680 . 10.1002/jcp.28387 . 73726197 . free .
6. Fujita T, Hayashida K, Shiba H, Kishimoto A, Matsuda S, Takeda K, Kawaguchi H, Kurihara H . The expressions of claudin-1 and E-cadherin in junctional epithelium . Journal of Periodontal Research . 45 . 4 . 579–82 . August 2010 . 20337884 . 10.1111/j.1600-0765.2009.01258.x .
7. Zhao Y, Yao J, Wu XP, Zhao L, Zhou YX, Zhang Y, You QD, Guo QL, Lu N . Wogonin suppresses human alveolar adenocarcinoma cell A549 migration in inflammatory microenvironment by modulating the IL-6/STAT3 signaling pathway . Molecular Carcinogenesis . 54 . E81-93 . June 2015 . Suppl 1 . 24976450 . 10.1002/mc.22182 . 29685898 .
8. Yu Z, Yu W, Liu J, Wu D, Wang C, Zhang J, Zhao J . Lens-specific deletion of the Msx2 gene increased apoptosis by enhancing the caspase-3/caspase-8 signaling pathway . The Journal of International Medical Research . 46 . 7 . 2843–2855 . July 2018 . 29921154 . 6124292 . 10.1177/0300060518774687 .
9. Melville H, Wang Y, Taub PJ, Jabs EW . Genetic basis of potential therapeutic strategies for craniosynostosis . American Journal of Medical Genetics. Part A . 152A . 12 . 3007–15 . December 2010 . 21082653 . 10.1002/ajmg.a.33703 . 24424024 . free .
10. Zhang H, Hu G, Wang H, Sciavolino P, Iler N, Shen MM, Abate-Shen C . Heterodimerization of Msx and Dlx homeoproteins results in functional antagonism . Molecular and Cellular Biology . 17 . 5 . 2920–32 . May 1997 . 9111364 . 232144 . 10.1128/mcb.17.5.2920 .