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.
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 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.
In this way the initial gradients of morphogens can lead to the establishment of a specific region within the blastoderm.
It can be compared to a narrow bandwidth filter in engineering.
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 has 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.
^Hoy MA (January 2019). "Genetic Systems, Genome Evolution, and Genetic Control of Embryonic Development in Insects". In Hoy MA (ed.). Insect Molecular Genetics. Academic Press. pp. 103–175. doi:10.1016/B978-0-12-815230-0.00004-2. ISBN9780128152300. {{cite book}}: |work= ignored (help)
^Nüsslein-Volhard C, Wieschaus E, Kluding H (September 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. PMID28305337. S2CID2195415.
^Wieschaus E, Nusslein-Volhard C, Kluding H (July 1984). "Krüppel, a gene whose activity is required early in the zygotic genome for normal embryonic segmentation". Developmental Biology. 104 (1): 172–86. doi:10.1016/0012-1606(84)90046-0. PMID6428949.
^Wei D, Gong W, Kanai M, Schlunk C, Wang L, Yao JC, et al. (April 2005). "Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression". Cancer Research. 65 (7): 2746–54. doi:10.1158/0008-5472.CAN-04-3619. PMID15805274.
^Pankratz MJ, Seifert E, Gerwin N, Billi B, Nauber U, Jäckle H (April 1990). "Gradients of Krüppel and knirps gene products direct pair-rule gene stripe patterning in the posterior region of the Drosophila embryo". Cell. 61 (2): 309–17. doi:10.1016/0092-8674(90)90811-R. PMID2331752. S2CID44716994.
^La Rosée-Borggreve A, Häder T, Wainwright D, Sauer F, Jäckle H (December 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): 133–40. doi:10.1016/s0925-4773(99)00219-1. hdl:11858/00-001M-0000-002A-18E2-F. PMID10559488. S2CID17728959.
^Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (November 2007). "Induction of pluripotent stem cells from adult human fibroblasts by defined factors". Cell. 131 (5): 861–72. doi:10.1016/j.cell.2007.11.019. hdl:2433/49782. PMID18035408. S2CID8531539.
Diagram at Davidson College - a Drosophila embryo at the cellular blastoderm stage triple-labeled for three segmentation proteins including Krüppel (in blue) Hairy (green) and Giant (red).
