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In situ hybridization against mRNA of the gap genes knirps, Krüppel and giant in the Drosophila melanogaster early embryo. Panels also show how these genes are affected by the mutation brakeless (bks).

Krüppel is a gap gene in Drosophila melanogaster, located on the 2R chromosome, which encodes a zinc finger C2H2 transcription factor.[1][2] Gap genes work together to establish the anterior-posterior segment patterning of the insect through regulation of the transcription factor encoding pair rule genes. These genes in turn regulate segment polarity genes.[3] Krüppel means "cripple" in German, named for the crippled appearance of mutant larvae, who have failed to develop proper thoracic and anterior segments in the abdominal region.[4][5][6] Mutants can also have abdominal mirror duplications.

Human homologs of Krüppel are collectively named Krüppel-like factors, a set of proteins well characterized for their role in carcinogenesis.[7][8][9][10][11]

Krüppel Expression Pathway  

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Krüppel is expressed in the center of the embryo during the cellular blastoderm stage of development.[12] Its expression pattern is restricted to this domain largely through interactions with the maternal effect genes Bicoid and Nanos, and fellow gap gene Hunchback and Knirps.[13]

Bicoid maternal transcripts are deposited at the anterior end of the embryo, while Nanos maternal transcripts are located at the posterior. Hunchback mRNA transcripts are present throughout the embryo. Bicoid and Nanos both encode morphogens that have the opposite effect on Hunchback mRNA translation – Bicoid activates translation, whereas Nanos represses it.[14] As such, Hunchback mRNA is translated so that Hunchback protein is present in the concentration gradient which decreases along the anterior – posterior axis. This Hunchback gradient indirectly results in an anterior boundary for Knirps expression. Other factors induce a posterior boundary, so that Knirps is expressed in a stripe in the posterior region of the embryo.

Hunchback and Knirps are both transcription factors that regulate Krüppel expression. High levels of Hunchback inhibit expression, whereas low levels of Hunchback activate expression. Knirps acts as a repressor to inhibit expression. This results in Krüppel being expressed in a stripe in the center of the embryo’s A-P axis, where Hunchback concentration has dropped to a low enough level so that it can act as an activator, but Knirps is not yet present to inhibit.  

Effects of Krüppel Expression

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The Krüppel protein is a transcription factor, and has been shown to act as a repressor. It functions in collaboration with other gap genes and their localized protein products to regulate the expression of the primary pair rule genes – even skipped (eve), hairy (h), and runt.[15] It’s been postulated that Krüppel inhibits eve expression to create the posterior boundary of eve stripe two, and evidence has also been found for Krüppel being a player specifically in the formation of hairy stripe 7.[16][17] The expression patterns of pair rule gene will in turn regulate the segment polarity genes, making Krüppel essential for proper development along the anterior posterior axis and segment identity.

Clinical Significance

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Krüppel has shown homology to the mammalian Krüppel-like factors, which play key biological roles in the pathogenesis of many human diseases: cancer,[18] obesity,[19] inflammatory disorders[20] and cardiovascular complications.[21] Moreover, KLFs are known to be involved in inducible pluripotent stem cells generation, and preservation of the pluripotent state of embryonic stem cells.[22][23][24]

See also

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References

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  1. ^ Kinzler, Kenneth W.; Ruppert, John M.; Bigner, Sandra H.; Vogelstein, Bert (1988). "The GLI gene is a member of the Kruppel family of zinc finger proteins". Nature. 332 (6162): 371–374. doi:10.1038/332371a0. ISSN 1476-4687.
  2. ^ "FlyBase Gene Report: Dmel\Kr". flybase.org. Retrieved 2019-10-08.
  3. ^ Hoy, Marjorie A. (2019-01-01), Hoy, Marjorie A. (ed.), "Chapter 4 - Genetic Systems, Genome Evolution, and Genetic Control of Embryonic Development in Insects", Insect Molecular Genetics (Fourth Edition), Academic Press, pp. 103–175, ISBN 9780128152300, retrieved 2019-10-08
  4. ^ Nüsslein-Volhard, C.; Wieschaus, E. (1980-10-30). "Mutations affecting segment number and polarity in Drosophila". Nature. 287 (5785): 795–801. doi:10.1038/287795a0. ISSN 0028-0836. PMID 6776413.
  5. ^ Nüsslein-Volhard, C.; Wieschaus, E.; Kluding, H. (1984). "Mutations affecting the pattern of the larval cuticle inDrosophila melanogaster : I. Zygotic loci on the second chromosome". Wilhelm Roux's Archives of Developmental Biology. 193 (5): 267–282. doi:10.1007/BF00848156. ISSN 0340-0794. PMID 28305337.
  6. ^ Wieschaus, E.; Nusslein-Volhard, C.; Kluding, H. (1984). "Krüppel, a gene whose activity is required early in the zygotic genome for normal embryonic segmentation". Developmental Biology. 104 (1): 172–186. doi:10.1016/0012-1606(84)90046-0. ISSN 0012-1606. PMID 6428949.
  7. ^ Schuh, Reinhard; Aicher, Wilhelm; Gaul, Ulrike; Côte, Serge; Preiss, Anette; Maier, Dieter; Seifert, Eveline; Nauber, Ulrich; Schröder, Christian; Kemler, Rolf; Jäckle, Herbert (1986-12-26). "A conserved family of nuclear proteins containing structural elements of the finger protein encoded by Krüppel, a Drosophila segmentation gene". Cell. 47 (6): 1025–1032. doi:10.1016/0092-8674(86)90817-2. ISSN 0092-8674.
  8. ^ Yori, Jennifer L.; Seachrist, Darcie D.; Johnson, Emhonta; Lozada, Kristen L.; Abdul-Karim, Fadi W.; Chodosh, Lewis A.; Schiemann, William P.; Keri, Ruth A. (2011). "Krüppel-like factor 4 inhibits tumorigenic progression and metastasis in a mouse model of breast cancer". Neoplasia (New York, N.Y.). 13 (7): 601–610. doi:10.1593/neo.11260. ISSN 1476-5586. PMC 3132846. PMID 21750654.
  9. ^ Lin, Ze-Shiang; Chu, Hsiao-Chien; Yen, Yi-Chen; Lewis, Brian C.; Chen, Ya-Wen (2012). "Krüppel-like factor 4, a tumor suppressor in hepatocellular carcinoma cells reverts epithelial mesenchymal transition by suppressing slug expression". PloS One. 7 (8): e43593. doi:10.1371/journal.pone.0043593. ISSN 1932-6203. PMC 3427336. PMID 22937066.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ Wei, Daoyan; Gong, Weida; Kanai, Masashi; Schlunk, Christian; Wang, Liwei; Yao, James C.; Wu, Tsung-Teh; Huang, Suyun; Xie, Keping (2005-04-01). "Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression". Cancer Research. 65 (7): 2746–2754. doi:10.1158/0008-5472.CAN-04-3619. ISSN 0008-5472. PMID 15805274.
  11. ^ Lee, Ursula E.; Ghiassi-Nejad, Zahra; Paris, Andrew J.; Yea, Steven; Narla, Goutham; Walsh, Martin; Friedman, Scott L. (2010-03-05). "Tumor suppressor activity of KLF6 mediated by downregulation of the PTTG1 oncogene". FEBS letters. 584 (5): 1006–1010. doi:10.1016/j.febslet.2010.01.049. ISSN 1873-3468. PMC 2827621. PMID 20116377.
  12. ^ Licht, J. D.; Grossel, M. J.; Figge, J.; Hansen, U. M. (1990-07-05). "Drosophila Krüppel protein is a transcriptional repressor". Nature. 346 (6279): 76–79. doi:10.1038/346076a0. ISSN 0028-0836. PMID 2114551.
  13. ^ Knipple, D. C.; Seifert, E.; Rosenberg, U. B.; Preiss, A.; Jäckle, H. (1985). "Spatial and temporal patterns of Krüppel gene expression in early Drosophila embryos". Nature. 317 (6032): 40–44. doi:10.1038/317040a0. ISSN 0028-0836. PMID 2412131.
  14. ^ Porcher, Aude; Dostatni, Nathalie (2010-03-09). "The Bicoid Morphogen System". Current Biology. 20 (5): R249–R254. doi:10.1016/j.cub.2010.01.026. ISSN 0960-9822.
  15. ^ Pankratz, Michael J.; Seifert, Eveline; Gerwin, Nicole; Billi, Bettina; Nauber, Ulrich; Jäckle, Herbert (1990-04-20). "Gradients of Krüppel and knirps gene products direct pair-rule gene stripe patterning in the posterior region of the drosophila embryo". Cell. 61 (2): 309–317. doi:10.1016/0092-8674(90)90811-R. ISSN 0092-8674.
  16. ^ Small, S.; Kraut, R.; Hoey, T.; Warrior, R.; Levine, M. (1991-05-01). "Transcriptional regulation of a pair-rule stripe in Drosophila". Genes & Development. 5 (5): 827–839. doi:10.1101/gad.5.5.827. ISSN 0890-9369. PMID 2026328.
  17. ^ La Rosée-Borggreve, A.; Häder, T.; Wainwright, D.; Sauer, F.; Jäckle, H. (1999). "hairy stripe 7 element mediates activation and repression in response to different domains and levels of Krüppel in the Drosophila embryo". Mechanisms of Development. 89 (1–2): 133–140. doi:10.1016/s0925-4773(99)00219-1. ISSN 0925-4773. PMID 10559488.
  18. ^ Ghaleb, A. M.; Katz, J. P.; Kaestner, K. H.; Du, J. X.; Yang, V. W. (2007-04-05). "Krüppel-like factor 4 exhibits antiapoptotic activity following gamma-radiation-induced DNA damage". Oncogene. 26 (16): 2365–2373. doi:10.1038/sj.onc.1210022. ISSN 0950-9232. PMC 2230633. PMID 17016435.
  19. ^ Brey, Christopher W.; Nelder, Mark P.; Hailemariam, Tiruneh; Gaugler, Randy; Hashmi, Sarwar (2009-10-01). "Krüppel-like family of transcription factors: an emerging new frontier in fat biology". International Journal of Biological Sciences. 5 (6): 622–636. doi:10.7150/ijbs.5.622. ISSN 1449-2288. PMC 2757581. PMID 19841733.
  20. ^ Hamik, Anne; Lin, Zhiyong; Kumar, Ajay; Balcells, Mercedes; Sinha, Sumita; Katz, Jonathan; Feinberg, Mark W.; Gerzsten, Robert E.; Edelman, Elazer R.; Jain, Mukesh K. (2007-05-04). "Kruppel-like factor 4 regulates endothelial inflammation". The Journal of Biological Chemistry. 282 (18): 13769–13779. doi:10.1074/jbc.M700078200. ISSN 0021-9258. PMID 17339326.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ Rajamannan, Nalini M.; Subramaniam, Malayannan; Abraham, Theodore P.; Vasile, Vlad C.; Ackerman, Michael J.; Monroe, David G.; Chew, Teng-Leong; Spelsberg, Thomas C. (2007-02-01). "TGFbeta inducible early gene-1 (TIEG1) and cardiac hypertrophy: Discovery and characterization of a novel signaling pathway". Journal of Cellular Biochemistry. 100 (2): 315–325. doi:10.1002/jcb.21049. ISSN 0730-2312. PMC 3927779. PMID 16888812.
  22. ^ Jiang, Jianming; Chan, Yun-Shen; Loh, Yuin-Han; Cai, Jun; Tong, Guo-Qing; Lim, Ching-Aeng; Robson, Paul; Zhong, Sheng; Ng, Huck-Hui (2008). "A core Klf circuitry regulates self-renewal of embryonic stem cells". Nature Cell Biology. 10 (3): 353–360. doi:10.1038/ncb1698. ISSN 1476-4679. PMID 18264089.
  23. ^ Nandan, Mandayam O.; Yang, Vincent W. (2009). "The role of Krüppel-like factors in the reprogramming of somatic cells to induced pluripotent stem cells". Histology and Histopathology. 24 (10): 1343–1355. doi:10.14670/HH-24.1343. ISSN 1699-5848. PMC 2753264. PMID 19688699.
  24. ^ Takahashi, Kazutoshi; Tanabe, Koji; Ohnuki, Mari; Narita, Megumi; Ichisaka, Tomoko; Tomoda, Kiichiro; Yamanaka, Shinya (2007-11-30). "Induction of pluripotent stem cells from adult human fibroblasts by defined factors". Cell. 131 (5): 861–872. doi:10.1016/j.cell.2007.11.019. ISSN 0092-8674. PMID 18035408.
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