The Iroquois family of genes was discovered inDrosophila during a mutagenesis experiment designed to identify genes that affected the development of external sensory organs. When genes of this family were knocked out, theDrosophila flies expressed a unique patterning of bristles reminiscent ofIroquois American Indians, they were subsequently named after them.[6] The molecular characteristics of these genes allowed the identification of homologs inC. elegans and several other vertebrates.[7]
IRX3 is a member of theIroquois homeobox gene family and plays a role in an early step of neural development.[8] Members of this family appear to play multiple roles during pattern formation of vertebrate embryos.[5][9]Specifically, IRX3 contributes to pattern formation in the spinal cord where it translates amorphogen gradient into transcriptional events, and is directly regulated byNKX2-2.[10] 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 toSonic 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.[11]
Irx3 is also expressed in the ventricles of the heart, where it regulates the postnatal maturation and electrophysiological function of the ventricular conduction system (VCS). Embryonically, it is expressed in ventricular trabeculae (which develop into Purkinje fibers of the VCS), and its expression is restricted to the VCS in the mature heart.[12] Its function is required for the rapid conduction characteristic of VCS components, and this is achieved by its indirect activation ofGja5-encoded Connexin-40, the major gap junction that facilitates rapid electrical propagation, and repression ofGja1-encoded Connexin-43. In the absence of Irx3, mice exhibit abnormal cardiac electrophysiology (prolonged QRS duration, notch in the R wave).[13][14] Additionally,IRX3 is associated with conduction defects in humans, such as Brugada syndrome and bundle branch block[15] (which is also observed in Irx3-/- mice).
Obesity-associated noncoding sequences withinFTO interact with the promoter of IRX3 and FTO in human, mouse, and zebrafish. Obesity-associatedsingle 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.[16] Manipulation of IRX3 and IRX5 pathways has also been shown to decrease obesity markers in human cell cultures.[17]Genetic variants of FTO and IRX3 genes are in highlinkage disequilibrium and are associated with obesity risk.[18]
IRX3 is aberrantly expressed in ~20% ofB-ALL, ~30% ofAML, and ~50% ofT-ALL.[19] Expression of IRX3 alone is able to immortalise hematopoetic stem and progenitor cells (HSPCs) in myeloid culture and induce lymphoid leukemiasin vivo. Focal deletions ofFTO intron8 occur in ~2% of adult and ~6% of paediatricT-ALL patients, resulting in aberrantIRX3 expression.[20] Usually the proximal promoter ofIRX3 is bound toFTO intron 8 forming a long-range 'promoter tether' that suppressesIRX3 expression. Recurrent deletions of this 'promoter tether' enables hijack of a distal developmentalsuper-enhancer causingIRX3 expression.[20] InAML,FTO intron 8 is also the location of acis-regulatory module consisting of clustered enhancer elements and a long non-coding RNA which regulatesIRX3 expression and impedes myeloid differentiation.[21] Together, these findings add to the complex regulatory relationship between theFTO andIRX3 genes
^Cavodeassi F, Modolell J, Gómez-Skarmeta JL (August 2001). "The Iroquois family of genes: from body building to neural patterning".Development.128 (15):2847–2855.doi:10.1242/dev.128.15.2847.hdl:10261/198505.PMID11532909.
^Cavodeassi F, Modolell J, Gómez-Skarmeta JL (August 2001). "The Iroquois family of genes: from body building to neural patterning".Development.128 (15):2847–2855.doi:10.1242/dev.128.15.2847.hdl:10261/198505.PMID11532909.
^Kim KH, Rosen A, Bruneau BG, Hui CC, Backx PH (May 2012). "Iroquois homeodomain transcription factors in heart development and function".Circulation Research.110 (11):1513–1524.doi:10.1161/CIRCRESAHA.112.265041.PMID22628575.
^Srivastava A, Mittal B, Prakash J, Srivastava P, Srivastava N, Srivastava N (September 2016). "Association of FTO and IRX3 genetic variants to obesity risk in north India".Annals of Human Biology.43 (5):451–456.doi:10.3109/03014460.2015.1103902.PMID26440677.S2CID19868664.
^abRahman S, Bloye G, Farah N, Demeulemeester J, Costa JR, O'Connor D, et al. (November 2024). "Focal deletions of a promoter tether activate the IRX3 oncogene in T-cell acute lymphoblastic leukemia".Blood.144 (22):2319–2326.doi:10.1182/blood.2024024300.PMID39316719.
