Early growth response protein 2 is a protein that in humans is encoded by the EGR2gene. EGR2 (also termed Krox20) is a transcription regulatory factor, containing two zinc finger DNA-binding sites, and is highly expressed in a population of migrating neural crest cells.[1][2][3] It is later expressed in the neural crest derived cells of the cranial ganglion. The protein encoded by Krox20 contains two cys2his2-type zinc fingers. Krox20 gene expression is restricted to the early hindbrain development.[2][4] It is evolutionarily conserved in vertebrates, humans, mice, chicks, and zebra fish.[5] In addition, the amino acid sequence and most aspects of the embryonic gene pattern is conserved among vertebrates, further implicating its role in hindbrain development.[3][6][7][8] When the Krox20 is deleted in mice, the protein coding ability of the Krox20 gene (including the DNA-binding domain of the zinc finger) is diminished. These mice are unable to survive after birth and exhibit major hindbrain defects.[2][4] These defects include but are not limited to defects in formation of cranial sensory ganglia, partial fusion of the trigeminal nerve (V) with the facial (VII) and auditory (VII) nerves, the proximal nerve roots coming off of these ganglia were disorganized and intertwined among one another as they entered the brainstem, and there was fusion of the glossopharyngeal (IX) nerve complex.[9][10][11]
The early growth response protein 2 is a transcription factor with three tandem C2H2-type zinc fingers. Mutations in this gene are associated with the autosomal dominant Charcot-Marie-Tooth disease, type 1D,[12]Dejerine–Sottas disease,[13] and Congenital Hypomyelinating Neuropathy.[14] Two studies have linked EGR2 expression to proliferation of osteoprogenitors [15] and cell lines derived from Ewing sarcoma, which is a highly aggressive bone-associated cancer.[16]
New research suggests that Krox20 - or the lack of it - is the reason for male baldness.[17]
↑ 2.02.12.2Swiatek PJ, Gridley T (November 1993). "Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20". Genes & Development. 7 (11): 2071–84. doi:10.1101/gad.7.11.2071. PMID8224839.
↑ 3.03.1Wilkinson DG, Bhatt S, Chavrier P, Bravo R, Charnay P (February 1989). "Segment-specific expression of a zinc-finger gene in the developing nervous system of the mouse". Nature. 337 (6206): 461–4. doi:10.1038/337461a0. PMID2915691.
↑ 4.04.1Bradley LC, Snape A, Bhatt S, Wilkinson DG (January 1993). "The structure and expression of the Xenopus Krox-20 gene: conserved and divergent patterns of expression in rhombomeres and neural crest". Mechanisms of Development. 40 (1–2): 73–84. doi:10.1016/0925-4773(93)90089-g. PMID8443108.
↑Bhat RV, Worley PF, Cole AJ, Baraban JM (April 1992). "Activation of the zinc finger encoding gene krox-20 in adult rat brain: comparison with zif268". Brain Research. Molecular Brain Research. 13 (3): 263–6. doi:10.1016/0169-328x(92)90034-9. PMID1317498.
↑Wilkinson DG, Bhatt S, Cook M, Boncinelli E, Krumlauf R (October 1989). "Segmental expression of Hox-2 homoeobox-containing genes in the developing mouse hindbrain". Nature. 341 (6241): 405–9. doi:10.1038/341405a0. PMID2571936.
↑Hunt P, Gulisano M, Cook M, Sham MH, Faiella A, Wilkinson D, Boncinelli E, Krumlauf R (October 1991). "A distinct Hox code for the branchial region of the vertebrate head". Nature. 353 (6347): 861–4. doi:10.1038/353861a0. PMID1682814.
↑Frohman MA, Boyle M, Martin GR (October 1990). "Isolation of the mouse Hox-2.9 gene; analysis of embryonic expression suggests that positional information along the anterior-posterior axis is specified by mesoderm". Development. 110 (2): 589–607. PMID1983472.
↑Murphy P, Davidson DR, Hill RE (September 1989). "Segment-specific expression of a homoeobox-containing gene in the mouse hindbrain". Nature. 341 (6238): 156–9. doi:10.1038/341156a0. PMID2571087.
↑Nieto MA, Bradley LC, Wilkinson DG (1991). "Conserved segmental expression of Krox-20 in the vertebrate hindbrain and its relationship to lineage restriction". Development. Suppl 2: 59–62. PMID1688180.
↑Boerkoel CF, Takashima H, Bacino CA, Daentl D, Lupski JR (July 2001). "EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy". Neurogenetics. 3 (3): 153–7. doi:10.1007/s100480100107. PMID11523566.
↑Warner LE, Mancias P, Butler IJ, McDonald CM, Keppen L, Koob KG, Lupski JR (April 1998). "Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies". Nature Genetics. 18 (4): 382–4. doi:10.1038/ng0498-382. PMID9537424.
Topilko P, Schneider-Maunoury S, Levi G, Baron-Van Evercooren A, Chennoufi AB, Seitanidou T, Babinet C, Charnay P (October 1994). "Krox-20 controls myelination in the peripheral nervous system". Nature. 371 (6500): 796–9. doi:10.1038/371796a0. PMID7935840.
Sham MH, Vesque C, Nonchev S, Marshall H, Frain M, Gupta RD, Whiting J, Wilkinson D, Charnay P, Krumlauf R (January 1993). "The zinc finger gene Krox20 regulates HoxB2 (Hox2.8) during hindbrain segmentation". Cell. 72 (2): 183–96. doi:10.1016/0092-8674(93)90659-E. PMID8093858.
Levi G, Topilko P, Schneider-Maunoury S, Lasagna M, Mantero S, Pesce B, Ghersi G, Cancedda R, Charnay P (June 1996). "Role of Krox-20 in endochondral bone formation". Annals of the New York Academy of Sciences. 785: 288–91. doi:10.1111/j.1749-6632.1996.tb56286.x. PMID8702157.
Warner LE, Mancias P, Butler IJ, McDonald CM, Keppen L, Koob KG, Lupski JR (April 1998). "Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies". Nature Genetics. 18 (4): 382–4. doi:10.1038/ng0498-382. PMID9537424.
Warner LE, Svaren J, Milbrandt J, Lupski JR (July 1999). "Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies". Human Molecular Genetics. 8 (7): 1245–51. doi:10.1093/hmg/8.7.1245. PMID10369870.
Timmerman V, De Jonghe P, Ceuterick C, De Vriendt E, Löfgren A, Nelis E, Warner LE, Lupski JR, Martin JJ, Van Broeckhoven C (June 1999). "Novel missense mutation in the early growth response 2 gene associated with Dejerine-Sottas syndrome phenotype". Neurology. 52 (9): 1827–32. doi:10.1212/wnl.52.9.1827. PMID10371530.
Bellone E, Di Maria E, Soriani S, Varese A, Doria LL, Ajmar F, Mandich P (October 1999). "A novel mutation (D305V) in the early growth response 2 gene is associated with severe Charcot-Marie-Tooth type 1 disease". Human Mutation. 14 (4): 353–4. doi:10.1002/(SICI)1098-1004(199910)14:4<353::AID-HUMU17>3.0.CO;2-4. PMID10502832.
Pareyson D, Taroni F, Botti S, Morbin M, Baratta S, Lauria G, Ciano C, Sghirlanzoni A (April 2000). "Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation". Neurology. 54 (8): 1696–8. doi:10.1212/wnl.54.8.1696. PMID10762521.
Gambardella L, Schneider-Maunoury S, Voiculescu O, Charnay P, Barrandon Y (September 2000). "Pattern of expression of the transcription factor Krox-20 in mouse hair follicle". Mechanisms of Development. 96 (2): 215–8. doi:10.1016/S0925-4773(00)00398-1. PMID10960786.
Yoshihara T, Kanda F, Yamamoto M, Ishihara H, Misu K, Hattori N, Chihara K, Sobue G (March 2001). "A novel missense mutation in the early growth response 2 gene associated with late-onset Charcot--Marie--Tooth disease type 1". Journal of the Neurological Sciences. 184 (2): 149–53. doi:10.1016/S0022-510X(00)00504-9. PMID11239949.
Boerkoel CF, Takashima H, Bacino CA, Daentl D, Lupski JR (July 2001). "EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy". Neurogenetics. 3 (3): 153–7. doi:10.1007/s100480100107. PMID11523566.
Yang Y, Dong B, Mittelstadt PR, Xiao H, Ashwell JD (May 2002). "HIV Tat binds Egr proteins and enhances Egr-dependent transactivation of the Fas ligand promoter". The Journal of Biological Chemistry. 277 (22): 19482–7. doi:10.1074/jbc.M201687200. PMID11909874.
Musso M, Balestra P, Taroni F, Bellone E, Mandich P (February 2003). "Different consequences of EGR2 mutants on the transactivation of human Cx32 promoter". Neurobiology of Disease. 12 (1): 89–95. doi:10.1016/S0969-9961(02)00018-9. PMID12609493.
Unoki M, Nakamura Y (April 2003). "EGR2 induces apoptosis in various cancer cell lines by direct transactivation of BNIP3L and BAK". Oncogene. 22 (14): 2172–85. doi:10.1038/sj.onc.1206222. PMID12687019.
Numakura C, Shirahata E, Yamashita S, Kanai M, Kijima K, Matsuki T, Hayasaka K (June 2003). "Screening of the early growth response 2 gene in Japanese patients with Charcot-Marie-Tooth disease type 1". Journal of the Neurological Sciences. 210 (1–2): 61–4. doi:10.1016/S0022-510X(03)00028-5. PMID12736090.
