IRX3 explained

Iroquois-class homeodomain protein IRX-3, also known as Iroquois homeobox protein 3, is a protein that in humans is encoded by the IRX3 gene.^[1]

Discovery and name

The Iroquois family of genes was discovered in Drosophila during a mutagenesis experiment designed to identify genes that affected the development of external sensory organs. When genes of this family were knocked out, the Drosophila flies expressed a unique patterning of bristles reminiscent of Iroquois American Indians, they were subsequently named after them.^[2] The molecular characteristics of these genes allowed the identification of homologs in C. elegans and several other vertebrates.^[3]

Function

IRX3 is a member of the Iroquois homeobox gene family and plays a role in an early step of neural development.^[4] Members of this family appear to play multiple roles during pattern formation of vertebrate embryos.^{[1] [5]} Specifically, IRX3 contributes to pattern formation in the spinal cord where it translates a morphogen gradient into transcriptional events, and is directly regulated by NKX2-2.^[6] The Irx3 gene controls the subdivision of the neural territory by working together with various other homeodomain factors, all of these factors are expressed in partially overlapping domains along the dorsoventral axis in response to Sonic hedgehog molecules emanating from the floor plate. The combination of these signals defines five regions, each of which will give rise to five types of neurons (V0, V1, V2, MN, and V3). For example, the region that generates V2 neurons expresses both Irx3 and Nkx6.1, while that which forms MN neurons expresses Nkx6.1 alone. Irx3 overexpression in the MN domain transforms MN into V2 neurons.^[7]

Clinical significance

Association with obesity

Obesity-associated noncoding sequences within FTO interact with the promoter of IRX3 and FTO in human, mouse, and zebrafish. Obesity-associated single nucleotide polymorphisms are related to the expression of IRX3 (not FTO) in the human brain. A direct connection between the expression of IRX3 and body mass and composition was shown through the decrease in body weight of 25-30% in IRX3-deficient mice. This suggests that IRX3 influences obesity.^[8] Manipulation of IRX3 and IRX5 pathways has also been shown to decrease obesity markers in human cell cultures.^[9] Genetic variants of FTO and IRX3 genes are in high linkage disequilibrium and are associated with obesity risk.^[10]

Further reading

• Trynka G, Zhernakova A, Romanos J, Franke L, Hunt KA, Turner G, Bruinenberg M, Heap GA, Platteel M, Ryan AW, de Kovel C, Holmes GK, Howdle PD, Walters JR, Sanders DS, Mulder CJ, Mearin ML, Verbeek WH, Trimble V, Stevens FM, Kelleher D, Barisani D, Bardella MT, McManus R, van Heel DA, Wijmenga C . Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling . Gut . 58 . 8 . 1078–1083 . August 2009 . 19240061 . 10.1136/gut.2008.169052 . 17111427 .
• Ragvin A, Moro E, Fredman D, Navratilova P, Drivenes Ø, Engström PG, Alonso ME, de la Calle Mustienes E, Gómez Skarmeta JL, Tavares MJ, Casares F, Manzanares M, van Heyningen V, Molven A, Njølstad PR, Argenton F, Lenhard B, Becker TS . Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3 . Proceedings of the National Academy of Sciences of the United States of America . 107 . 2 . 775–780 . January 2010 . 20080751 . 2818943 . 10.1073/pnas.0911591107 . free . 2010PNAS..107..775R .

Notes and References

1. Web site: Entrez Gene: iroquois homeobox 3.
2. Chaudière CD, Leyns L . The determination of sense organs in Drosophila: a search for interacting genes. . The International Journal of Developmental Biology . 1992 . 36 . 85–91 .
3. Cavodeassi F, Modolell J, Gómez-Skarmeta JL . The Iroquois family of genes: from body building to neural patterning . Development . 128 . 15 . 2847–2855 . August 2001 . 11532909 . 10.1242/dev.128.15.2847 . free . 10261/198505 .
4. Bellefroid EJ, Kobbe A, Gruss P, Pieler T, Gurdon JB, Papalopulu N . Xiro3 encodes a Xenopus homolog of the Drosophila Iroquois genes and functions in neural specification . The EMBO Journal . 17 . 1 . 191–203 . January 1998 . 9427753 . 1170370 . 10.1093/emboj/17.1.191 .
5. Lewis MT, Ross S, Strickland PA, Snyder CJ, Daniel CW . Regulated expression patterns of IRX-2, an Iroquois-class homeobox gene, in the human breast . Cell and Tissue Research . 296 . 3 . 549–554 . June 1999 . 10370142 . 10.1007/s004410051316 . 37046813 .
6. Lovrics A, Gao Y, Juhász B, Bock I, Byrne HM, Dinnyés A, Kovács KA . Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord . PloS One . 9 . 11 . e111430 . November 2014 . 25398016 . 4232242 . 10.1371/journal.pone.0111430 . free . 2014PLoSO...9k1430L .
7. Cavodeassi F, Modolell J, Gómez-Skarmeta JL . The Iroquois family of genes: from body building to neural patterning . Development . 128 . 15 . 2847–2855 . August 2001 . 11532909 . 10.1242/dev.128.15.2847 . free . 10261/198505 .
8. Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gómez-Marín C, Aneas I, Credidio FL, Sobreira DR, Wasserman NF, Lee JH, Puviindran V, Tam D, Shen M, Son JE, Vakili NA, Sung HK, Naranjo S, Acemel RD, Manzanares M, Nagy A, Cox NJ, Hui CC, Gomez-Skarmeta JL, Nóbrega MA . Obesity-associated variants within FTO form long-range functional connections with IRX3 . Nature . 507 . 7492 . 371–375 . March 2014 . 24646999 . 4113484 . 10.1038/nature13138 . 2014Natur.507..371S .
9. Claussnitzer M, Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C, Glunk V, Sousa IS, Beaudry JL, Puviindran V, Abdennur NA, Liu J, Svensson PA, Hsu YH, Drucker DJ, Mellgren G, Hui CC, Hauner H, Kellis M . FTO Obesity Variant Circuitry and Adipocyte Browning in Humans . The New England Journal of Medicine . 373 . 10 . 895–907 . September 2015 . 26287746 . 4959911 . 10.1056/NEJMoa1502214 .
   • News: Bartlett J . 20 August 2015 . MIT, Harvard find 'master switch' behind obesity . .
10. Srivastava A, Mittal B, Prakash J, Srivastava P, Srivastava N, Srivastava N . Association of FTO and IRX3 genetic variants to obesity risk in north India . Annals of Human Biology . 43 . 5 . 451–456 . September 2016 . 26440677 . 10.3109/03014460.2015.1103902 . 19868664 .