Homeobox
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A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. Mutations in a homeobox may change large-scale anatomical features of the full-grown organism.
Homeoboxes are found within
Discovery
The existence of homeobox genes was first discovered in
Homeodomain structure
The characteristic homeodomain
Helix 1 Helix 2 Helix 3/4
______________ __________ _________________
RRRKRTAYTRYQLLELEKEFHFNRYLTRRRRIELAHSLNLTERHIKIWFQNRRMKWKKEN
....|....|....|....|....|....|....|....|....|....|....|....|
10 20 30 40 50 60
Helix 2 and helix 3 form a so-called
Homeodomain proteins are found in
Sequence specificity
Homeodomains can bind both specifically and nonspecifically to
Biological function
Homeodomain proteins function as
Regulation
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
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.
Evolution
The homeobox itself may have evolved from a non-DNA-binding transmembrane domain at the C-terminus of the MraY enzyme. This is based on metagenomic data acquired from the transitional archaeon,
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.[22] 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.[23] 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.[24] Gene duplication followed by neofunctionalization is responsible for the many homeobox genes found in eukaryotes.[25][26] Comparison of homeobox genes and gene clusters has been used to understand the evolution of genome structure and body morphology throughout metazoans.[27]
Types of homeobox genes
Hox genes
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.[30]
In vertebrates, the four
LIM genes
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.[46]
Pax genes
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.[47] 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.[48]
POU genes
Proteins containing a POU region consist of a homeodomain and a separate,
Plant homeobox genes
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.[25] Conservation of codomains suggests a common eukaryotic ancestry for TALE[49] and non-TALE homeodomain proteins.[50]
Human homeobox genes
The Hox genes in humans are organized in four chromosomal clusters:
| name | chromosome | gene |
| HOXA (or sometimes HOX1) - HOXA@ | chromosome 7 |
|
| HOXB - HOXB@ | chromosome 17 | HOXB1, HOXB2, HOXB3, HOXB4, HOXB5, HOXB6, HOXB7, HOXB8, HOXB9, HOXB13 |
| HOXC - HOXC@ | chromosome 12 | HOXC4, HOXC5, HOXC6, HOXC8, HOXC9, HOXC10, HOXC11, HOXC12, HOXC13 |
| HOXD - HOXD@ | chromosome 2 | HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD10, HOXD11, HOXD12, HOXD13 |
ParaHox genes are analogously found in four areas. They include CDX1, CDX2, CDX4; GSX1, GSX2; and PDX1. Other genes considered Hox-like include EVX1, EVX2; GBX1, GBX2; MEOX1, MEOX2; and MNX1. The NK-like (NKL) genes, some of which are considered "MetaHox", are grouped with Hox-like genes into a large ANTP-like group.[51][52]
Humans have a
Human TALE (Three Amino acid Loop Extension) homeobox genes for an "atypical" homeodomain consist of 63 rather than 60 amino acids:
In addition, humans have the following homeobox genes and proteins:[51]
- LIM-class: ISL1, ISL2; LHX1, LHX2, LHX3, LHX4, LHX5, LHX6, LHX8, LHX9;[a] LMX1A, LMX1B
- POU-class:
- CERS-class: ;
- HNF-class: HNF1B;
- SINE-class:
- CUT-class: ;
- ZF-class: ;
- PRD-class:
- NKL-class: ;
- Nkx: ;
See also
References
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- ^ Materials for the study of variation, treated with especial regard to discontinuity in the origin of species William Bateson 1861–1926. London : Macmillan 1894 xv, 598 p
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Further reading
- Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, et al. (2003). Molecular Cell Biology (5th ed.). New York: W.H. Freeman and Company. ISBN 978-0-7167-4366-8.
- Tooze C, Branden J (1999). Introduction to protein structure (2nd ed.). New York: Garland Pub. pp. 159–66. ISBN 978-0-8153-2305-1.
- Ogishima S, Tanaka H (January 2007). "Missing link in the evolution of Hox clusters". Gene. 387 (1–2): 21–30. PMID 17098381.
External links
- The Homeodomain Resource (National Human Genome Research Institute, National Institutes of Health)
- HomeoDB: a database of homeobox genes diversity. Zhong YF, Butts T, Holland PWH, since 2008. Archived 2021-06-01 at the Wayback Machine
- Eukaryotic Linear Motif resource motif class LIG_HOMEOBOX
- Homeobox at the U.S. National Library of Medicine Medical Subject Headings (MeSH)