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.
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. Expression of msx2 leads to the proliferation, migration and osteogenic differentiation of neural crest cells during embryogenesis and bone fracture. 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. 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. 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.
^Takahashi C, Akiyama N, Matsuzaki T, Takai S, Kitayama H, Noda M (May 1996). "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. PMID8668339.
^Kostrzewa M, Grady DL, Moyzis RK, Flöter L, Müller U (March 1996). "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. doi:10.1007/BF02185781. PMID8786091. S2CID12647370.
^Liu H, Chen B, Li Y (March 2019). "microRNA-203 promotes proliferation, differentiation, and migration of osteoblasts by upregulation of Msh homeobox 2". Journal of Cellular Physiology. 234 (10): 17639–17648. doi:10.1002/jcp.28387. PMID30854680. S2CID73726197.
^Fujita T, Hayashida K, Shiba H, Kishimoto A, Matsuda S, Takeda K, Kawaguchi H, Kurihara H (August 2010). "The expressions of claudin-1 and E-cadherin in junctional epithelium". Journal of Periodontal Research. 45 (4): 579–82. doi:10.1111/j.1600-0765.2009.01258.x. PMID20337884.
^Zhao Y, Yao J, Wu XP, Zhao L, Zhou YX, Zhang Y, You QD, Guo QL, Lu N (June 2015). "Wogonin suppresses human alveolar adenocarcinoma cell A549 migration in inflammatory microenvironment by modulating the IL-6/STAT3 signaling pathway". Molecular Carcinogenesis. 54 Suppl 1: E81-93. doi:10.1002/mc.22182. PMID24976450. S2CID29685898.
^Melville H, Wang Y, Taub PJ, Jabs EW (December 2010). "Genetic basis of potential therapeutic strategies for craniosynostosis". American Journal of Medical Genetics. Part A. 152A (12): 3007–15. doi:10.1002/ajmg.a.33703. PMID21082653. S2CID24424024.
Suzuki M, Tanaka M, Iwase T, Naito Y, Sugimura H, Kino I (July 1993). "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. doi:10.1006/bbrc.1993.1802. hdl:10271/1007. PMID7687426.
Semenza GL, Wang GL, Kundu R (April 1995). "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. doi:10.1006/bbrc.1995.1497. PMID7726844.
Hodgkinson JE, Davidson CL, Beresford J, Sharpe PT (July 1993). "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. doi:10.1016/0167-4781(93)90086-s. PMID8101453.
Jabs EW, Müller U, Li X, Ma L, Luo W, Haworth IS, Klisak I, Sparkes R, Warman ML, Mulliken JB (November 1993). "A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis". Cell. 75 (3): 443–50. doi:10.1016/0092-8674(93)90379-5. PMID8106171. S2CID13650758.
Quinn LM, Johnson BV, Nicholl J, Sutherland GR, Kalionis B (March 1997). "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. doi:10.1016/S0378-1119(96)00706-8. PMID9073066.
Stelnicki EJ, Kömüves LG, Holmes D, Clavin W, Harrison MR, Adzick NS, Largman C (October 1997). "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. doi:10.1046/j.1432-0436.1997.6210033.x. PMID9373945.
Iimura T, Takeda K, Goseki M, Maruoka Y, Sasaki S, Oida S (1998). "Characterization of two length cDNA for human MSX-2 from dental pulp-derived cells". DNA Sequence. 8 (1–2): 87–92. doi:10.3109/10425179709020891. PMID9522127.
Newberry EP, Latifi T, Towler DA (August 1999). "The RRM domain of MINT, a novel Msx2 binding protein, recognizes and regulates the rat osteocalcin promoter". Biochemistry. 38 (33): 10678–90. doi:10.1021/bi990967j. PMID10451362.
Wilkie AO, Tang Z, Elanko N, Walsh S, Twigg SR, Hurst JA, Wall SA, Chrzanowska KH, Maxson RE (April 2000). "Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification". Nature Genetics. 24 (4): 387–90. doi:10.1038/74224. PMID10742103. S2CID21030594.
Quinn LM, Latham SE, Kalionis B (2000). "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. doi:10.1053/plac.1999.0514. PMID10831122.