Hox gene
Hox genes, a subset of homeobox genes, are a group of related genes 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, 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.
Producing Hox proteins
The products of Hox genes are Hox proteins. Hox proteins are a subset of transcription factors, which are proteins that are capable of binding to specific nucleotide sequences on DNA called enhancers through which they either activate or repress hundreds of other genes. The same Hox protein can act as a repressor at one gene and an activator at another. The ability of Hox proteins to bind DNA is conferred by a part of the protein referred to as the homeodomain. The homeodomain is a 60-amino-acid-long DNA-binding domain. This amino acid sequence folds into a "helix-turn-helix" motif that is stabilized by a third helix. The consensus polypeptide chain is shown below: Hox proteins often act in partnership with co-factors, such as PBC and Meis proteins encoded by very different types of homeobox gene.Helix 1 Helix 2 Helix 3/4
______________ __________ _________________
RRRKRTAYTRYQLLELEKEFLFNRYLTRRRRIELAHSLNLTERHIKIWFQNRRMKWKKEN
....|....|....|....|....|....|....|....|....|....|....|....|
10 20 30 40 50 60
Evolution
Homeobox genes, and thus the homeodomain protein motif, are found in most eukaryotes. The Hox genes, being a subset of homeobox genes, arose more recently in evolution within the animal kingdom or Metazoa. Within the animal kingdom, Hox genes are present across the bilateria, and have also been found in Cnidaria such as sea anemones. This implies that Hox genes arose over 550 million years ago. In bilateria, Hox genes are often arranged in gene clusters, although there are many exceptions where the genes have been separated by chromosomal rearrangements. Comparing homeodomain sequences between Hox proteins often reveals greater similarity between species than within a species; this observation led to the conclusion that Hox gene clusters evolved early in animal evolution from a single Hox gene via tandem duplication and subsequent divergence, and that a prototypic Hox gene cluster containing at least seven different Hox genes was present in the common ancestor of all bilaterian animals.In most bilaterian animals, 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.
In ''Drosophila''
Drosophila melanogaster is an important model organism for understanding body plan generation and evolution. The general principles of Hox gene function and logic elucidated in flies will apply to all bilaterian organisms, including humans. Drosophila, like all insects, has eight Hox genes. These are clustered into two complexes, both of which are located on chromosome 3. The Antennapedia complex consists of five genes: labial, proboscipedia, deformed, sex combs reduced, and Antennapedia. The Bithorax complex, named after the Ultrabithorax gene, consists of the remaining three genes: Ultrabithorax, abdominal-A and abdominal-B.Labial
The lab gene is the most anteriorly expressed gene. It is expressed in the head, primarily in the intercalary segment, and also in the midgut. Loss of function of lab results in the failure of the Drosophila embryo to internalize the mouth and head structures that initially develop on the outside of its body. Failure of head involution disrupts or deletes the salivary glands and pharynx. The lab gene was initially so named because it disrupted the labial appendage; however, the lab gene is not expressed in the labial segment, and the labial appendage phenotype is likely a result of the broad disorganization resulting from the failure of head involution.Proboscipedia
The pb gene is responsible for the formation of the labial and maxillary palps. Some evidence shows pb interacts with Scr.Deformed
The Dfd gene is responsible for the formation of the maxillary and mandibular segments in the larval head. The mutant phenotypes of Dfd are similar to those of labial. Loss of function of Dfd in the embryo results in a failure of head involution, with a loss of larval head structures. Mutations in the adult have either deletions of parts of the head or transformations of head to thoracic identity.Sex combs reduced
The Scr gene is responsible for cephalic and thoracic development in Drosophila embryo and adult.Antennapedia
The second thoracic segment, or T2, develops a pair of legs and a pair of wings. The Antp gene specifies this identity by promoting leg formation and allowing wing formation. A dominant Antp mutation, caused by a chromosomal inversion, causes Antp to be expressed in the antennal imaginal disc, so that, instead of forming an antenna, the disc makes a leg, resulting in a leg coming out of the fly's head.Ultrabithorax
The third thoracic segment, or T3, bears a pair of legs and a pair of halteres. Ubx patterns T3 largely by repressing genes involved in wing formation. The wing blade is composed of two layers of cells that adhere tightly to one another, and are supplied with nutrient by several wing veins. One of the many genes that Ubx represses is blistered, which activates proteins involved in cell-cell adhesion, and spalt, which patterns the placement of wing veins. In Ubx loss-of-function mutants, Ubx no longer represses wing genes, and the halteres develop as a second pair of wings, resulting in the famous four-winged flies. When Ubx is misexpressed in the second thoracic segment, such as occurs in flies with the "Cbx" enhancer mutation, it represses wing genes, and the wings develop as halteres, resulting in a four-haltered fly.Abdominal-A
In Drosophila, abd-A is expressed along most of the abdomen, from abdominal segments 1 to A8. Expression of abd-A is necessary to specify the identity of most of the abdominal segments. A major function of abd-A in insects is to repress limb formation. In abd-A loss-of-function mutants, abdominal segments A2 through A8 are transformed into an identity more like A1. When abd-A is ectopically expressed throughout the embryo, all segments anterior of A4 are transformed to an A4-like abdominal identity.The abd-A gene also affects the pattern of cuticle generation in the ectoderm, and pattern of muscle generation in the mesoderm.
Abdominal-B
Gene abd-B is transcribed in two different forms, a regulatory protein, and a morphogenic protein. Regulatory abd-B suppress embryonic ventral epidermal structures in the eighth and ninth segments of the Drosophila abdomen. Both the regulatory protein and the morphogenic protein are involved in the development of the tail segment.Classification of Hox proteins
Proteins with a high degree of sequence similarity are also generally assumed to exhibit a high degree of functional similarity, i.e. Hox proteins with identical homeodomains are assumed to have identical DNA-binding properties.To identify the set of proteins between two different species that are most likely to be most similar in function, classification schemes are used. For Hox proteins, three different classification schemes exist: phylogenetic inference based, synteny-based, and sequence similarity-based. The three classification schemes provide conflicting information for Hox proteins expressed in the middle of the body axis. A combined approach used phylogenetic inference-based information of the different species and plotted the protein sequence types onto the phylogenetic tree of the species. The approach identified the proteins that best represent ancestral forms and the proteins that represent new, derived versions.