Homeobox

            Helix 1          Helix 2         Helix 3/4
         ______________    __________    _________________
RRRKRTAYTRYQLLELEKEFHFNRYLTRRRRIELAHSLNLTERHIKIWFQNRRMKWKKEN
....|....|....|....|....|....|....|....|....|....|....|....|
         10        20        30        40        50        60

Helix 2 and helix 3 form a so-called

Hox genes and their associated microRNAs are highly conserved developmental master regulators with tight tissue-specific, spatiotemporal control. These genes are known to be dysregulated in several cancers and are often controlled by DNA methylation.^[18][19] The regulation of Hox genes is highly complex and involves reciprocal interactions, mostly inhibitory. Drosophila is known to use the polycomb and trithorax complexes to maintain the expression of Hox genes after the down-regulation of the pair-rule and gap genes that occurs during larval development. Polycomb-group proteins can silence the Hox genes by modulation of chromatin structure.^[20]

Mutations to homeobox genes can produce easily visible phenotypic changes in body segment identity, such as the Antennapedia and Bithorax mutant phenotypes in Drosophila. Duplication of homeobox genes can produce new body segments, and such duplications are likely to have been important in the evolution of segmented animals.

Phylogenetic analysis of homeobox gene sequences and homeodomain protein structures suggests that the last common ancestor of plants, fungi, and animals had at least two homeobox genes.^[21] Molecular evidence shows that some limited number of Hox genes have existed in the Cnidaria since before the earliest true Bilatera, making these genes pre-Paleozoic.^[22] It is accepted that the three major animal ANTP-class clusters, Hox, ParaHox, and NK (MetaHox), are the result of segmental duplications. A first duplication created MetaHox and ProtoHox, the latter of which later duplicated into Hox and ParaHox. The clusters themselves were created by tandem duplications of a single ANTP-class homeobox gene.^[23] Gene duplication followed by neofunctionalization is responsible for the many homeobox genes found in eukaryotes.^[24][25] Comparison of homeobox genes and gene clusters has been used to understand the evolution of genome structure and body morphology throughout metazoans.^[26]

Hox genes are the most commonly known subset of homeobox genes. They are essential

Mutations in these homeotic genes cause displacement of body segments during embryonic development. This is called ectopia. For example, when one gene is lost the segment develops into a more anterior one, while a mutation that leads to a gain of function causes a segment to develop into a more posterior one. Famous examples are Antennapedia and bithorax in Drosophila, which can cause the development of legs instead of antennae and the development of a duplicated thorax, respectively.^[29]

In vertebrates, the four

LIM genes (named after the initial letters of the names of three proteins where the characteristic domain was first identified) encode two 60 amino acid cysteine and histidine-rich LIM domains and a homeodomain. The LIM domains function in protein-protein interactions and can bind zinc molecules. LIM domain proteins are found in both the cytosol and the nucleus. They function in cytoskeletal remodeling, at focal adhesion sites, as scaffolds for protein complexes, and as transcription factors.^[45]

Most Pax genes contain a homeobox and a paired domain that also binds DNA to increase binding specificity, though some Pax genes have lost all or part of the homeobox sequence.^[46] Pax genes function in embryo segmentation, nervous system development, generation of the frontal eye fields, skeletal development, and formation of face structures. Pax 6 is a master regulator of eye development, such that the gene is necessary for development of the optic vesicle and subsequent eye structures.^[47]

Proteins containing a POU region consist of a homeodomain and a separate,

As in animals, the plant homeobox genes code for the typical 60 amino acid long DNA-binding homeodomain or in case of the TALE (three amino acid loop extension) homeobox genes for an atypical homeodomain consisting of 63 amino acids. According to their conserved intron–exon structure and to unique codomain architectures they have been grouped into 14 distinct classes: HD-ZIP I to IV, BEL, KNOX, PLINC, WOX, PHD, DDT, NDX, LD, SAWADEE and PINTOX.[24] Conservation of codomains suggests a common eukaryotic ancestry for TALE^[48] and non-TALE homeodomain proteins.^[49]

The Hox genes in humans are organized in four chromosomal clusters:

In addition, humans have the following homeobox genes and proteins:[50]

• LIM-class: ISL1, ISL2; LHX1, LHX2, LHX3, LHX4, LHX5, LHX6, LHX8, LHX9;^[a] LMX1A, LMX1B
• POU-class:
  POU5F1; POU5F1P1; POU5F1P4; POU5F2; POU6F1; and POU6F2
• CERS-class:
  LASS2, LASS3, LASS4, LASS5, LASS6
  ;
• HNF-class:
  HNF1B
  ;
• SINE-class:
  SIX1, SIX2, SIX3, SIX4, SIX5, SIX6^[b]
• CUT-class:
  CUX1, CUX2; SATB1, SATB2
  ;
• ZF-class:
  ZFHX3, ZFHX4; ZHX1, HOMEZ
  ;
• PRD-class:
  RAX, RAX2; RHOXF1, RHOXF2/2B; SEBOX; SHOX, SHOX2; TPRX1; UNCX; VSX1, VSX2
• NKL-class:
  MSX2; NANOG; NOTO; TLX1, TLX2, TLX3; TSHZ1, TSHZ2, TSHZ3; VAX1, VAX2, VENTX
  ;
  • Nkx:
    NKX2-5, NKX2-6;^[e] HMX1, HMX2, HMX3;^[f] NKX6-1; NKX6-2; NKX6-3
    ;

• Evolutionary developmental biology
• Body plan