Hox genes, a subset of
homeobox gene
A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. For instance, mutations in a homeobox may change large-scale anatomical features of the full-g ...
s, 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 (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
Hemichordata is a phylum which consists of triploblastic, enterocoelomate, and bilaterally symmetrical marine deuterostome animals, generally considered the sister group of the echinoderms. They appear in the Lower or Middle Cambrian and includ ...
species ''Schizocardium californicum'' and the pilidium larva of
Nemertea
Nemertea is a phylum of animals also known as ribbon worms or proboscis worms, consisting of 1300 known species. Most ribbon worms are very slim, usually only a few millimeters wide, although a few have relatively short but wide bodies. Many h ...
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
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
. 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
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
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
Metaplasia ( gr, "change in form") is the transformation of one differentiated cell type to another differentiated cell type. The change from one type of cell to another may be part of a normal maturation process, or caused by some sort of abno ...
and predisposes to oncological disease, e.g.
Barrett’s esophagus
Barrett's esophagus is a condition in which there is an abnormal ( metaplastic) change in the mucosal cells lining the lower portion of the esophagus, from stratified squamous epithelium to simple columnar epithelium with interspersed goblet cells ...
is the result of altered Hox coding and is a precursor to
esophageal cancer.
Biochemical function
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
In genetics, an enhancer is a short (50–1500 bp) region of DNA that can be bound by proteins ( activators) to increase the likelihood that transcription of a particular gene will occur. These proteins are usually referred to as transcriptio ...
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
A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. For instance, mutations in a homeobox may change large-scale anatomical features of the full ...
. The homeodomain is a 60-
amino-acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ami ...
-long DNA-binding domain (encoded by its corresponding 180-
base-pair
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
DNA sequence, the homeobox). This amino acid sequence folds into a "helix-turn-helix" (i.e.
homeodomain fold
A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. For instance, mutations in a homeobox may change large-scale anatomical features of the full-g ...
) 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
Conservation
![Arthropod segment Hox gene expression](https://upload.wikimedia.org/wikipedia/commons/a/ac/Arthropod_segment_Hox_gene_expression.svg)
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
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
within the animal kingdom or
Metazoa
Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in ...
. Within the animal kingdom, Hox genes are present across the
bilateria[ (animals with a clear head-to-tail axis), and have also been found in ]Cnidaria
Cnidaria () is a phylum under kingdom Animalia containing over 11,000 species of aquatic animals found both in freshwater and marine environments, predominantly the latter.
Their distinguishing feature is cnidocytes, specialized cells that ...
such as sea anemones
Sea anemones are a group of predatory marine invertebrates of the order Actiniaria. Because of their colourful appearance, they are named after the ''Anemone'', a terrestrial flowering plant. Sea anemones are classified in the phylum Cnidaria, ...
.[ 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
Duplication, duplicate, and duplicator may refer to:
Biology and genetics
* Gene duplication, a process which can result in free mutation
* Chromosomal duplication, which can cause Bloom and Rett syndrome
* Polyploidy, a phenomenon also known ...
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
In biology and genetic genealogy, the most recent common ancestor (MRCA), also known as the last common ancestor (LCA) or concestor, of a set of organisms is the most recent individual from which all the organisms of the set are descended. The ...
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
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
'' is an important model 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 (not to be confused with the ''Antp'' gene) consists of five genes: labial (''lab''), proboscipedia (''pb''), deformed (''Dfd''), sex combs reduced (''Scr''), and Antennapedia (''Antp''). The Bithorax complex, named after the Ultrabithorax gene, consists of the remaining three genes: Ultrabithorax (''Ubx''), abdominal-A (''abd-A'') and abdominal-B (''abd-B'').
Labial
The ''lab'' gene is the most anteriorly expressed gene. It is expressed in the head, primarily in the intercalary segment (an appendageless segment between the antenna and mandible), 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 (a process called head involution). 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 (see labial gene), 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 (but not directly activating) 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 (highly reduced wings that function in balancing during flight). ''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 (A1) 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 (unless additional sequences are known to influence DNA-binding).
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 (''Hox6-8'' and ''Antp, Ubx'' and'' abd-A''). 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 (''Hox7'' and ''Antp'') and the proteins that represent new, derived versions (or were lost in an ancestor and are now missing in numerous species).
Genes regulated by Hox proteins
Hox genes act at many levels within developmental gene hierarchies: at the "executive" level they regulate genes that in turn regulate large networks of other genes (like the gene pathway that forms an appendage). They also directly regulate what are called realisator genes or effector genes that act at the bottom of such hierarchies to ultimately form the tissues, structures, and organs of each segment. Segmentation involves such processes as morphogenesis (differentiation of precursor cells into their terminal specialized cells), the tight association of groups of cells with similar fates, the sculpting of structures and segment boundaries via programmed cell death, and the movement of cells from where they are first born to where they will ultimately function, so it is not surprising that the target genes of Hox genes promote cell division, cell adhesion, apoptosis, and cell migration.
Enhancer sequences bound by homeodomains
The DNA sequence bound by the homeodomain protein contains the nucleotide sequence TAAT, with the 5' terminal T being the most important for binding. This sequence is conserved in nearly all sites recognized by homeodomains, and probably distinguishes such locations as DNA binding sites. The base pairs following this initial sequence are used to distinguish between homeodomain proteins, all of which have similar recognition sites. For instance, the nucleotide following the TAAT sequence is recognized by the amino acid at position 9 of the homeodomain protein. In the maternal protein Bicoid, this position is occupied by lysine, which recognizes and binds to the nucleotide guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is c ...
. In Antennapedia, this position is occupied by glutamine
Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
, which recognizes and binds to adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deri ...
. If the lysine in Bicoid is replaced by glutamine, the resulting protein will recognize Antennapedia-binding enhancer sites.
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.
Regulation of Hox genes
Just as Hox genes regulate realisator genes, they are in turn regulated themselves by other genes. In Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
and some insects (but not most animals), Hox genes are regulated by gap gene
A gap gene is a type of gene involved in the development of the segmented embryos of some arthropods. Gap genes are defined by the effect of a mutation in that gene, which causes the loss of contiguous body segments, resembling a gap in the norm ...
s and pair-rule gene
A pair-rule gene is a type of gene involved in the development of the segmented embryos of insects. Pair-rule genes are expressed as a result of differing concentrations of gap gene proteins, which encode transcription factors controlling pair- ...
s, which are in their turn regulated by maternally-supplied mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
. This results in a transcription factor cascade: maternal factors activate gap or pair-rule genes; gap and pair-rule genes activate Hox genes; then, finally, Hox genes activate realisator genes that cause the segments in the developing embryo to differentiate.
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
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. mi ...
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
A non-coding RNA (ncRNA) is a functional RNA molecule that is not Translation (genetics), translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally im ...
(ncRNA) has been shown to be abundant in Hox clusters. In humans, 231 ncRNA may be present. One of these, HOTAIR
HOTAIR (for HOX transcript antisense RNA) is a human gene located between HOXC11 and HOXC12 on chromosome 12. It is the first example of an RNA expressed on one chromosome that has been found to influence transcription of HOXD cluster posterio ...
, silences in trans (it is transcribed from the HOXC cluster and inhibits late HOXD genes) by binding to Polycomb-group proteins
Polycomb-group proteins (PcG proteins) are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox genes ...
(PRC2).
The chromatin
Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
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
Retinoic acid (used simplified here for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that mediates the functions of vitamin A1 required for growth and development. All-''trans''-retinoic acid is required in ...
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.
Collinearity
In some organisms, especially vertebrates, the various Hox genes are situated very close to one another on the chromosome in groups or clusters. The order of the genes on the chromosome is the same as the expression of the genes in the developing embryo, with the first gene being expressed in the anterior end of the developing organism. The reason for this colinearity is not yet completely understood, but could be related to the activation of Hox genes in a temporal sequence by gradual unpacking of chromatin along a gene cluster. The diagram above shows the relationship between the genes and protein expression in flies.
Nomenclature
The Hox genes are named for the homeotic phenotypes that result when their function is disrupted, wherein one segment develops with the identity of another (e.g. legs where antennae should be). Hox genes in different phyla have been given different names, which has led to confusion about nomenclature. The complement of Hox genes in ''Drosophila'' is made up of two clusters, the Antennapedia complex and the Bithorax complex, which together were historically referred to as the HOM-C (for Homeotic Complex). Although historically HOM-C genes have referred to ''Drosophila'' homologues, while Hox genes referred to vertebrate homologues, this distinction is no longer made, and both HOM-C and Hox genes are called Hox genes.
In other species
Vertebrates
Mice and humans have 39 Hox genes in four clusters:
The ancestors of vertebrates had a single Hox gene cluster, which was duplicated (twice) early in vertebrate evolution by whole genome duplication
Paleopolyploidy is the result of genome duplications which occurred at least several million years ago (MYA). Such an event could either double the genome of a single species (autopolyploidy) or combine those of two species (allopolyploidy). Bec ...
s 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 lampreys
Lampreys (sometimes inaccurately called lamprey eels) are an ancient extant lineage of jawless fish of the order Petromyzontiformes , placed in the superclass Cyclostomata. The adult lamprey may be characterized by a toothed, funnel-like su ...
and hagfish
Hagfish, of the class Myxini (also known as Hyperotreti) and order Myxiniformes , are eel-shaped, slime-producing marine fish (occasionally called slime eels). They are the only known living animals that have a skull but no vertebral column, ...
from other vertebrates. Most tetrapods
Tetrapods (; ) are four-limbed vertebrate animals constituting the superclass Tetrapoda (). It includes extant and extinct amphibians, sauropsids (reptiles, including dinosaurs and therefore birds) and synapsids ( pelycosaurs, extinct therapsi ...
have four HOX clusters, while most teleost fish
Teleostei (; Greek ''teleios'' "complete" + ''osteon'' "bone"), members of which are known as teleosts ), is, by far, the largest infraclass in the class Actinopterygii, the ray-finned fishes, containing 96% of all extant species of fish. Tel ...
, including zebrafish
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...
and medaka
The Japanese rice fish (''Oryzias latipes''), also known as the medaka, is a member of genus ''Oryzias'' ( ricefish), the only genus in the subfamily Oryziinae. This small (up to about ) native of East Asia is a denizen of rice paddies, marshes, ...
, have seven or eight Hox gene clusters because of an additional genome duplication
Polyploidy is a condition in which the cells of an organism have more than one pair of ( homologous) chromosomes. Most species whose cells have nuclei ( eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set contain ...
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
]Vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...
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 somites
The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryonic stage of somitogenesis, along the head-to-tail axis in segmented animals. In vertebrates, somites subdivide i ...
, which form the vertebrae and ribs, the dermis of the dorsal skin, the skeletal muscles
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...
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 invertebrates
Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordat ...
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
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
, in particular, has to do with the location and layering of HOX genes within the genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
. Vertebrates do have HOX genes that are homologous to those of the fly as it is one of the most highly conserved genes, 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 gene arrays (A–D) on four separate chromosomes
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
, whereas there are eight HOX genes in total for the Drosophila. Clusters are far more redundant and less likely to generate mutations. In flies, one gene can be mutated, resulting in a haltere
''Halteres'' (; singular ''halter'' or ''haltere'') (from grc, ἁλτῆρες, weights held in the hands to give an impetus in leaping) are a pair of small club-shaped organs on the body of two orders of flying insects that provide info ...
, 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
In evolutionary biology, adaptive radiation is a process in which organisms diversify rapidly from an ancestral species into a multitude of new forms, particularly when a change in the environment makes new resources available, alters biotic int ...
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 phyla. All of the paralogous
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
genes need to be knocked out in order for there to be any phenotypic
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
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 don’t grow ribs, and inactive in the mid-back, allowing ribs to be formed. When the HOX10 paralogs
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
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.
Amphioxus
Amphioxus
The lancelets ( or ), also known as amphioxi (singular: amphioxus ), consist of some 30 to 35 species of "fish-like" benthic filter feeding chordates in the order Amphioxiformes. They are the modern representatives of the subphylum Cephalochorda ...
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 roundworm
The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-parasitic nematodes also known as eelworms. They are a diverse animal phylum inhabiting a bro ...
. '' Hydra'' and ''Nematostella vectensis
The starlet sea anemone (''Nematostella vectensis'') is a species of small sea anemone in the family Edwardsiidae native to the east coast of the United States, with introduced populations along the coast of southeast England and the west coast o ...
'', both in the phylum Cnidaria
Cnidaria () is a phylum under kingdom Animalia containing over 11,000 species of aquatic animals found both in freshwater and marine environments, predominantly the latter.
Their distinguishing feature is cnidocytes, specialized cells that ...
, have a few Hox/ParaHox-like homeobox genes.
Hox gene expression has also been studied in brachiopods
Brachiopods (), phylum Brachiopoda, are a phylum of trochozoan animals that have hard "valves" (shells) on the upper and lower surfaces, unlike the left and right arrangement in bivalve molluscs. Brachiopod valves are hinged at the rear end, wh ...
, annelids
The annelids (Annelida , from Latin ', "little ring"), also known as the segmented worms, are a large phylum, with over 22,000 extant species including ragworms, earthworms, and leeches. The species exist in and have adapted to various ecolog ...
, and a suite of molluscs
Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of which are known as molluscs or mollusks (). Around 85,000 extant species of molluscs are recognized. The number of fossil species is estim ...
.
History
The Hox genes are so named because mutations in them cause homeotic transformations. Homeotic transformations were first identified and studied by William Bateson
William Bateson (8 August 1861 – 8 February 1926) was an English biologist who was the first person to use the term genetics to describe the study of heredity, and the chief populariser of the ideas of Gregor Mendel following their rediscove ...
in 1894, who coined the term "homeosis". After the rediscovery of 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.
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
Thomas Hunt Morgan (September 25, 1866 – December 4, 1945) was an American evolutionary biologist, geneticist, embryologist, and science author who won the Nobel Prize in Physiology or Medicine in 1933 for discoveries elucidating the role that ...
'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
Christiane (Janni) Nüsslein-Volhard (; born 20 October 1942) is a German developmental biologist and a 1995 Nobel Prize in Physiology or Medicine laureate. She is the only woman from Germany to have received a Nobel Prize in the sciences.
N ...
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
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
in 1995.
In 1983, the homeobox was discovered independently by researchers in two labs: Ernst Hafen, Michael Levine, and William McGinnis
William McGinnis, Ph.Dis a molecular biology, molecular biologist and professor of biology at the University of California San Diego. At UC San Diego he has also served as the Chairman of the Department of Biology from July 1998 - June 1999, as ...
(in Walter Gehring
Walter Jakob Gehring (20 March 1939 – 29 May 2014) was a Swiss developmental biologist who was a professor at the Biozentrum Basel of the University of Basel, Switzerland. He obtained his PhD at the University of Zurich in 1965 and after two ...
's lab at the University of Basel
The University of Basel (Latin: ''Universitas Basiliensis'', German: ''Universität Basel'') is a university in Basel, Switzerland. Founded on 4 April 1460, it is Switzerland's oldest university and among the world's oldest surviving universit ...
, Switzerland) and Matthew P. Scott and Amy Weiner (in Thomas Kaufman's lab at Indiana University in Bloomington).
Future
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
* Homeotic gene In evolutionary developmental biology, homeotic genes are genes which regulate the development of anatomical structures in various organisms such as echinoderms, insects, mammals, and plants. Homeotic genes often encode transcription factor proteins ...
* Hox genes in amphibians and reptiles
* Morphogenesis
Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...
* Discredited hypotheses for the Cambrian explosion (Section: Regulatory genes)
References
Further reading
*
{{DEFAULTSORT:Hox Gene
Developmental genes and proteins
Gene clusters
Evolutionary developmental biology