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 residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''IRX3''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
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 ( or ), officially the Haudenosaunee ( meaning "people of the longhouse"), are an Iroquoian-speaking confederacy of First Nations peoples in northeast North America/ Turtle Island. They were known during the colonial years to ...
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 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.
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. Manipulation of IRX3 and IRX5 pathways has also been shown to decrease obesity markers in human cell cultures.
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Genetic variants of FTO and IRX3 genes are in high
linkage disequilibrium
In population genetics, linkage disequilibrium (LD) is the non-random association of alleles at different loci in a given population. Loci are said to be in linkage disequilibrium when the frequency of association of their different alleles is h ...
and are associated with obesity risk.
References
Further reading
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