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Hox genes, a subset of homeobox, are a gene cluster that specify regions of the body plan of an embryo along the head-tail axis of animals. Hox proteins encode and specify the characteristics of 'position', ensuring that the correct structures form in the correct places of the body. For example, Hox genes in insects specify which appendages form on a segment (for example, legs, antennae, and wings in fruit flies), and Hox genes in vertebrates specify the types and shape of vertebrae that will form. In segmented animals, Hox proteins thus confer segmental or positional identity, but do not form the actual segments themselves.
Studies on Hox genes in ciliated larvae have shown they are only expressed in future adult tissues. In larvae with gradual metamorphosis the Hox genes are activated in tissues of the larval body, generally in the trunk region, that will be maintained through metamorphosis. In larvae with complete metamorphosis the Hox genes are mainly expressed in juvenile rudiments and are absent in the transient larval tissues. The larvae of the hemichordate species Schizocardium californicum and the pilidium larva of Nemertea do not express Hox genes.
An analogy for the Hox genes can be made to the role of a play director who calls which scene the actors should carry out next. If the play director calls the scenes in the wrong order, the overall play will be presented in the wrong order. Similarly, mutations in the Hox genes can result in body parts and limbs in the wrong place along the body. Like a play director, the Hox genes do not act in the play or participate in limb formation themselves.
The protein product of each Hox gene is a transcription factor. Each Hox gene contains a well-conserved DNA sequence known as the homeobox, of which the term "Hox" was originally a contraction. However, in current usage the term Hox is no longer equivalent to homeobox, because Hox genes are not the only genes to possess a homeobox sequence; for instance, humans have over 200 homeobox genes, of which 39 are Hox genes. Hox genes are thus a subset of the homeobox transcription factor genes. In many animals, the organization of the Hox genes in the chromosome is the same as the order of their expression along the anterior-posterior axis of the developing animal, and are thus said to display colinearity. Production of Hox gene products at wrong location in the body is associated with metaplasia and predisposes to oncological disease, e.g. Barrett's esophagus is the result of altered Hox coding and is a precursor to esophageal cancer.
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In most Bilateria, Hox genes are expressed in staggered domains along the head-to-tail axis of the embryo, suggesting that their role in specifying position is a shared, ancient feature. The functional conservation of Hox proteins can be demonstrated by the fact that a fly can function to a large degree with a chicken Hox protein in place of its own. So, despite having a last common ancestor that lived over 550 million years ago, the chicken and fly version of the same Hox gene are similar enough to target the same downstream genes in flies.
However, all homeodomain-containing transcription factors bind essentially the same DNA sequence. The sequence bound by the homeodomain of a Hox protein is only six nucleotides long, and such a short sequence would be found at random many times throughout the genome, far more than the number of actual functional sites. Especially for Hox proteins, which produce such dramatic changes in morphology when misexpressed, this raises the question of how each transcription factor can produce such specific and different outcomes if they all bind the same sequence. One mechanism that introduces greater DNA sequence specificity to Hox proteins is to bind protein cofactors. Two such Hox cofactors are Extradenticle (Exd) and Homothorax (Hth). Exd and Hth bind to Hox proteins and appear to induce conformational changes in the Hox protein that increase its specificity. (2025). 9780123745293 ISBN 9780123745293
Regulation is achieved via protein concentration gradients, called morphogenic fields. For example, high concentrations of one maternal protein and low concentrations of others will turn on a specific set of gap or pair-rule genes. In flies, stripe 2 in the embryo is activated by the maternal proteins Bicoid and Hunchback, but repressed by the gap proteins Giant and Kruppel. Thus, stripe 2 will only form wherever there is Bicoid and Hunchback, but not where there is Giant and Kruppel.
MicroRNA strands located in Hox clusters have been shown to inhibit more anterior hox genes ("posterior prevalence phenomenon"), possibly to better fine tune its expression pattern.
Non-coding RNA (ncRNA) has been shown to be abundant in Hox clusters. In humans, 231 ncRNA may be present. One of these, HOTAIR, silences in trans (it is transcribed from the HOXC cluster and inhibits late HOXD genes) by binding to Polycomb-group proteins (PRC2).
The chromatin structure is essential for transcription but it also requires the cluster to loop out of the chromosome territory.
In higher animals including humans, retinoic acid regulates differential expression of Hox genes along the anteroposterior axis. Genes in the 3' ends of Hox clusters are induced by retinoic acid resulting in expression domains that extend more anteriorly in the body compared to 5' Hox genes that are not induced by retinoic acid resulting in expression domains that remain more posterior.
Quantitative PCR has shown several trends regarding colinearity: the system is in equilibrium and the total number of transcripts depends on the number of genes present according to a linear relationship.
| HOXA1, HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXA10, HOXA11, HOXA13 |
| HOXB1, HOXB2, HOXB3, HOXB4, HOXB5, HOXB6, HOXB7, HOXB8, HOXB9, HOXB13 |
| HOXC4, HOXC5, HOXC6, HOXC8, HOXC9, HOXC10, HOXC11, HOXC12, HOXC13 |
| HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD10, HOXD11, HOXD12, HOXD13 |
The ancestors of vertebrates had a single Hox gene cluster,Spagnuolo, A., Ristoratore, F., Di Gregorio, A., Aniello, F., Branno, M. & Di Lauro, R. (2003) Gene 309, 71–79 which was duplicated (twice) early in vertebrate evolution by whole genome duplications to give four Hox gene clusters: Hoxa, Hoxb, Hoxc and Hoxd. It is currently unclear whether these duplications occurred before or after the divergence of and hagfish from other vertebrates. Most have four HOX clusters, while most teleost fish, including zebrafish and medaka, have seven or eight Hox gene clusters because of an additional genome duplication which occurred in their evolutionary history. In zebrafish, one of the eight Hox gene clusters (a Hoxd cluster) has lost all protein-coding genes, and just a single microRNA gene marks the location of the original cluster. In some teleost fish, such as salmon, an even more recent genome duplication occurred, doubling the seven or eight Hox gene clusters to give at least 13 clusters Another teleost, the freshwater butterflyfish, has instead seen a significant loss in HOX gene clusters, with only 5 clusters present.
Vertebrate bodies are not segmented in the same way as insects; they are on average much more complex, leading to more infrastructure in their body plan compared to insects. HOX genes control the regulation and development of many key structures in the body, such as , which form the vertebrae and ribs, the dermis of the dorsal skin, the of the back, and the skeletal muscles of the body wall and limbs. HOX genes help differentiate somite cells into more specific identities and direct them to develop differently depending on where they are in the body. A large difference between vertebrates and is the location and layering of HOX genes. The fundamental mechanisms of development are strongly conserved among vertebrates from fish to mammals.
Due to the fact that the HOX genes are so highly conserved, most research has been done on much simpler model organisms, such as mice. One of the major differences that was noticed when comparing mice and drosophila, in particular, has to do with the location and layering of HOX genes within the genome. Vertebrates do have HOX genes that are homologous to those of the fly as it is one of the most highly conserved , but the location is different. For example, there are more HOX genes on the 5' side of the mouse segment compared to the invertebrates. These genes correspond to expression in the tail, which would make sense as flies would not have anything similar to the tail that all vertebrates have. Additionally, in most vertebrates there are 39 members segregated into four separate tightly clustered DNA microarray (A–D) on four separate , whereas there are eight HOX genes in total for the Drosophila. Gene cluster are far more redundant and less likely to generate . In flies, one gene can be mutated, resulting in a Halteres, something fundamental for them to be able to fly, being transformed into a wing, or an antenna turning into a leg; in the mouse, two to four genes must be simultaneously removed to get a similar complete transformation. Some researchers believe that, because of the redundancy of the vertebrate HOX cluster plan and more constrained compared to invertebrate HOX clusters, the evolvability of vertebrate HOX clusters is, for some structural or functional reason, far lower than their invertebrate counterparts. This rapid evolvability is in part because invertebrates experienced much more dramatic episodes of adaptive radiation and mutations. More than 20 major clades of invertebrates differ so radically in body organization, partly due to a higher mutation rate, that they became formally classified as different Phylum. All of the paralogous genes need to be knocked out in order for there to be any Phenotype changes for the most part. This is also one reason why homeotic mutations in vertebrates are so rarely seen.
In mouse embryos, the HOX10 genes, which is one of the genes that lie in the tail portion of the animal, turn the "rib-building" system off when the gene is activated. The genes are active in the lower back, where the vertebrae do not grow ribs, and inactive in the mid-back, allowing ribs to be formed. When the HOX10 paralogs are experimentally inactivated, the vertebrae of the lower back grow ribs. This research prompted an evolutionary search for these mutations among all animals. An example of this is in lizards and snakes. In snakes, HOX10 genes have lost their rib-blocking ability in that way.
Hox gene expression has also been studied in brachiopods, annelids, and a suite of molluscs.
Definitive evidence for a genetic basis of some homeotic transformations was obtained by isolating homeotic mutants. The first homeotic mutant was found by Calvin Bridges in Thomas Hunt Morgan's laboratory in 1915. This mutant shows a partial duplication of the thorax and was therefore named Bithorax ( bx). It transforms the third thoracic segment (T3) toward the second (T2). Bithorax arose spontaneously in the laboratory and has been maintained continuously as a laboratory stock ever since.
The genetic studies by Morgan and others provided the foundation for the systematic analyses of Edward B. Lewis and Thomas Kaufman, which provided preliminary definitions of the many homeotic genes of the Bithorax and Antennapedia complexes, and also showed that the mutant phenotypes for most of these genes could be traced back to patterning defects in the embryonic body plan.
Ed Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus identified and classified 15 genes of key importance in determining the body plan and the formation of body segments of the fruit fly D. melanogaster in 1980. For their work, Lewis, Nüsslein-Volhard, and Wieschaus were awarded the Nobel Prize in Physiology or Medicine in 1995.
In 1983, the homeobox was discovered independently by researchers in two labs: Ernst Hafen, Michael Levine, and William McGinnis (in Walter Gehring's lab at the University of Basel, Switzerland) and Matthew P. Scott and Amy Weiner (in Thomas Kaufman's lab at Indiana University in Bloomington).
Amphioxus
Amphioxus such as Branchiostoma floridae have a single Hox cluster with 15 genes, known as AmphiHox1 to AmphiHox15.
Other invertebrates
Six Hox genes are dispersed in the genome of Caenorhabditis elegans, a Nematode. Hydra and Nematostella vectensis, both in the phylum Cnidaria, have a few Hox/ParaHox-like homeobox genes.
History
The Hox genes are so named because mutations in them cause homeosis. Homeotic transformations were first identified and studied by William Bateson in 1894, who coined the term "homeosis". After the rediscovery of Gregor Mendel's genetic principles, Bateson and others realized that some examples of homeosis in floral organs and animal skeletons could be attributed to variation in genes.
Research
Hox genes play critical roles in the development of structures such as limbs, lungs, the nervous system, and eyes. As T. R. Lappin and colleagues observed in 2006, "Evolutionary conservation provides unlimited scope for experimental investigation of the functional control of the Hox gene network which is providing important insights into human disease." In the future, more research can be done in investigating the roles of Hox genes in leukaemia and cancer (such as EOC).
See also
Further reading
(1998). 9781559388160, Elsevier. ISBN 9781559388160
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