EGR2 explained

Early growth response protein 2 is a protein that in humans is encoded by the EGR2 gene. EGR2 (also termed Krox20) is a transcription regulatory factor, containing three zinc finger DNA-binding sites, and is highly expressed in a population of migrating neural crest cells. 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. It is evolutionarily conserved in vertebrates, humans, mice, chicks, and zebra fish. 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. 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. 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.

Function

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,^[1] Dejerine–Sottas disease,^[2] and Congenital Hypomyelinating Neuropathy.^[3] Two studies have linked EGR2 expression to proliferation of osteoprogenitors ^[4] and cell lines derived from Ewing sarcoma, which is a highly aggressive bone-associated cancer.^[5]

New research suggests that Krox20 - or the lack of it - is the reason for male baldness.^[6]

Further reading

• Rangnekar VM, Aplin AC, Sukhatme VP . The serum and TPA responsive promoter and intron-exon structure of EGR2, a human early growth response gene encoding a zinc finger protein . Nucleic Acids Research . 18 . 9 . 2749–57 . May 1990 . 2111009 . 330760 . 10.1093/nar/18.9.2749 .
• Chavrier P, Janssen-Timmen U, Mattéi MG, Zerial M, Bravo R, Charnay P . Structure, chromosome location, and expression of the mouse zinc finger gene Krox-20: multiple gene products and coregulation with the proto-oncogene c-fos . Molecular and Cellular Biology . 9 . 2 . 787–97 . February 1989 . 2496302 . 362656 . 10.1128/mcb.9.2.787 .
• Joseph LJ, Le Beau MM, Jamieson GA, Acharya S, Shows TB, Rowley JD, Sukhatme VP . Molecular cloning, sequencing, and mapping of EGR2, a human early growth response gene encoding a protein with "zinc-binding finger" structure . Proceedings of the National Academy of Sciences of the United States of America . 85 . 19 . 7164–8 . October 1988 . 3140236 . 282144 . 10.1073/pnas.85.19.7164 . 1988PNAS...85.7164J . free .
• Topilko P, Schneider-Maunoury S, Levi G, Baron-Van Evercooren A, Chennoufi AB, Seitanidou T, Babinet C, Charnay P . Krox-20 controls myelination in the peripheral nervous system . Nature . 371 . 6500 . 796–9 . October 1994 . 7935840 . 10.1038/371796a0 . 1994Natur.371..796T . 4333028 .
• Sham MH, Vesque C, Nonchev S, Marshall H, Frain M, Gupta RD, Whiting J, Wilkinson D, Charnay P, Krumlauf R . The zinc finger gene Krox20 regulates HoxB2 (Hox2.8) during hindbrain segmentation . Cell . 72 . 2 . 183–96 . January 1993 . 8093858 . 10.1016/0092-8674(93)90659-E . 3205209 .
• Levi G, Topilko P, Schneider-Maunoury S, Lasagna M, Mantero S, Pesce B, Ghersi G, Cancedda R, Charnay P . Role of Krox-20 in endochondral bone formation . Annals of the New York Academy of Sciences . 785 . 1. 288–91 . June 1996 . 8702157 . 10.1111/j.1749-6632.1996.tb56286.x . 1996NYASA.785..288L . 27761983 .
• Warner LE, Mancias P, Butler IJ, McDonald CM, Keppen L, Koob KG, Lupski JR . Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies . Nature Genetics . 18 . 4 . 382–4 . April 1998 . 9537424 . 10.1038/ng0498-382 . 25550479 .
• Warner LE, Svaren J, Milbrandt J, Lupski JR . 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 . July 1999 . 10369870 . 10.1093/hmg/8.7.1245 . free .
• Timmerman V, De Jonghe P, Ceuterick C, De Vriendt E, Löfgren A, Nelis E, Warner LE, Lupski JR, Martin JJ, Van Broeckhoven C . Novel missense mutation in the early growth response 2 gene associated with Dejerine-Sottas syndrome phenotype . Neurology . 52 . 9 . 1827–32 . June 1999 . 10371530 . 10.1212/wnl.52.9.1827 . 11569651 .
• Bellone E, Di Maria E, Soriani S, Varese A, Doria LL, Ajmar F, Mandich P . 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 . October 1999 . 10502832 . 10.1002/(SICI)1098-1004(199910)14:4<353::AID-HUMU17>3.0.CO;2-4 . 85039222 . free .
• Pareyson D, Taroni F, Botti S, Morbin M, Baratta S, Lauria G, Ciano C, Sghirlanzoni A . Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation . Neurology . 54 . 8 . 1696–8 . April 2000 . 10762521 . 10.1212/wnl.54.8.1696 . 2434/531868 . 28404231 . free .
• Gambardella L, Schneider-Maunoury S, Voiculescu O, Charnay P, Barrandon Y . Pattern of expression of the transcription factor Krox-20 in mouse hair follicle . Mechanisms of Development . 96 . 2 . 215–8 . September 2000 . 10960786 . 10.1016/S0925-4773(00)00398-1 . 18000564 . free .
• Yoshihara T, Kanda F, Yamamoto M, Ishihara H, Misu K, Hattori N, Chihara K, Sobue G . 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 . March 2001 . 11239949 . 10.1016/S0022-510X(00)00504-9 . 19693658 .
• Boerkoel CF, Takashima H, Bacino CA, Daentl D, Lupski JR . EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy . Neurogenetics . 3 . 3 . 153–7 . July 2001 . 11523566 . 10.1007/s100480100107 . 32746701 .
• Yang Y, Dong B, Mittelstadt PR, Xiao H, Ashwell JD . HIV Tat binds Egr proteins and enhances Egr-dependent transactivation of the Fas ligand promoter . The Journal of Biological Chemistry . 277 . 22 . 19482–7 . May 2002 . 11909874 . 10.1074/jbc.M201687200 . free .
• Vandenberghe N, Upadhyaya M, Gatignol A, Boutrand L, Boucherat M, Chazot G, Vandenberghe A, Latour P . Frequency of mutations in the early growth response 2 gene associated with peripheral demyelinating neuropathies . Journal of Medical Genetics . 39 . 12 . 81e–81 . December 2002 . 12471219 . 1757229 . 10.1136/jmg.39.12.e81 .
• Musso M, Balestra P, Taroni F, Bellone E, Mandich P . Different consequences of EGR2 mutants on the transactivation of human Cx32 promoter . Neurobiology of Disease . 12 . 1 . 89–95 . February 2003 . 12609493 . 10.1016/S0969-9961(02)00018-9 . 29600641 .
• Unoki M, Nakamura Y . EGR2 induces apoptosis in various cancer cell lines by direct transactivation of BNIP3L and BAK . Oncogene . 22 . 14 . 2172–85 . April 2003 . 12687019 . 10.1038/sj.onc.1206222 . free .
• Numakura C, Shirahata E, Yamashita S, Kanai M, Kijima K, Matsuki T, Hayasaka K . 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 . June 2003 . 12736090 . 10.1016/S0022-510X(03)00028-5 . 36723641 .

External links

• GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 1
• GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 4

Notes and References

1. Web site: Entrez Gene: EGR2 early growth response 2 (Krox-20 homolog, Drosophila).
2. Boerkoel CF, Takashima H, Bacino CA, Daentl D, Lupski JR . EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy . Neurogenetics . 3 . 3 . 153–7 . July 2001 . 11523566 . 10.1007/s100480100107 . 32746701 .
3. Warner LE, Mancias P, Butler IJ, McDonald CM, Keppen L, Koob KG, Lupski JR . Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies . Nature Genetics . 18 . 4 . 382–4 . April 1998 . 9537424 . 10.1038/ng0498-382 . 25550479 .
4. Chandra A, Lan S, Zhu J, Siclari VA, Qin L . Epidermal growth factor receptor (EGFR) signaling promotes proliferation and survival in osteoprogenitors by increasing early growth response 2 (EGR2) expression . en . The Journal of Biological Chemistry . 288 . 28 . 20488–98 . July 2013 . 23720781 . 3711314 . 10.1074/jbc.M112.447250 . free .
5. Grünewald TG, Bernard V, Gilardi-Hebenstreit P, Raynal V, Surdez D, Aynaud MM, Mirabeau O, Cidre-Aranaz F, Tirode F, Zaidi S, Perot G, Jonker AH, Lucchesi C, Le Deley MC, Oberlin O, Marec-Bérard P, Véron AS, Reynaud S, Lapouble E, Boeva V, Rio Frio T, Alonso J, Bhatia S, Pierron G, Cancel-Tassin G, Cussenot O, Cox DG, Morton LM, Machiela MJ, Chanock SJ, Charnay P, Delattre O . 6 . Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite . Nature Genetics . 47 . 9 . 1073–8 . September 2015 . 26214589 . 4591073 . 10.1038/ng.3363 .
6. Web site: Le. Lu. Scientists find skin cells at the root of balding, gray hair. UT Southwestern Medical Center. 9 May 2017.