IRX3
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Iroquois-class homeodomain protein IRX-3, also known as Iroquois homeobox protein 3, is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''IRX3''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.


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 The Iroquois ( ), also known as the Five Nations, and later as the Six Nations from 1722 onwards; alternatively referred to by the Endonym and exonym, endonym Haudenosaunee ( ; ) are an Iroquoian languages, Iroquoian-speaking Confederation#Ind ...
American Indians, they were subsequently named after them. The molecular characteristics of these genes allowed the identification of homologs in ''C. elegans'' and several other vertebrates.


Function

IRX3 is a member of the Iroquois homeobox gene family and plays a role in an early step of neural development. Members of this family appear to play multiple roles during pattern formation of vertebrate embryos. Specifically, IRX3 contributes to pattern formation in the spinal cord where it translates a
morphogen A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various ...
gradient into transcriptional events, and is directly regulated by NKX2-2. 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 Sonic hedgehog protein (SHH) is a major signaling molecule of embryonic development in humans and animals, encoded by the ''SHH'' gene. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organoge ...
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. 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. Its function is required for the rapid conduction characteristic of VCS components, and this is achieved by its indirect activation of ''Gja5''-encoded Connexin-40, the major gap junction that facilitates rapid electrical propagation, and repression of ''Gja1''-encoded Connexin-43. In the absence of Irx3, mice exhibit abnormal cardiac electrophysiology (prolonged QRS duration, notch in the R wave). Additionally, ''IRX3'' is associated with conduction defects in humans, such as Brugada syndrome and bundle branch block (which is also observed in Irx3-/- mice).


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 In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
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. Manipulation of IRX3 and IRX5 pathways has also been shown to decrease obesity markers in human cell cultures. * Genetic variants of FTO and IRX3 genes are in high
linkage disequilibrium Linkage disequilibrium, often abbreviated to LD, is a term in population genetics referring to the association of genes, usually linked genes, in a population. It has become an important tool in medical genetics and other fields In defining LD, it ...
and are associated with obesity risk.


References


Further reading

* * {{Transcription factors, g3