Homeotic Selector Gene
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Homeotic selector genes confer segment identity 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 species ...
''. They encode
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-g ...
proteins which interact with Hox and other
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 ...
s to initiate segment-specific gene regulation. Homeodomain proteins are transcription factors that share a DNA-binding domain called the homeodomain. Changes in the expression and function of homeotic genes are responsible for the changes in the morphology of the limbs of arthropods as well as in the axial skeletons of vertebrates. Mutations in homeotic selector genes do not lead to elimination of a segment or pattern, but instead cause the segment to develop incorrectly.


History

The homeotic selector genes were discovered through the genetic analysis of
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 species ...
over 80 years ago . Unusual disturbances were found in the organization of the adult fly, resulting in misplaced limbs, such as legs developing where antennae usually develop or an extra pair of wings developing where halteres should be. This discovery provided a glimpse to understanding how each segment acquires its individual identity. The first homeotic gene cluster, the bithorax complex, was discovered by
Edward B. Lewis Edward Butts Lewis (May 20, 1918 – July 21, 2004) was an American geneticist, a corecipient of the 1995 Nobel Prize in Physiology or Medicine. He helped to found the field of evolutionary developmental biology. Early life Lewis was born in Wi ...
in 1978. Similar mutations in the complex were found to cluster together, leading Lewis to propose that these homeotic genes arose through a duplication mechanism which would conserve the clusters through evolution.bithorax complex The Bithorax complex (BX-C) is one of two ''Drosophila melanogaster '' homeotic gene complexes, located on the right arm of chromosome 3. It is responsible for the differentiation of the posterior two-thirds (posterior thorax and each abdominal ...
of Drosophila an exceptional Hox cluster"> The independent discoveries of the
homeobox 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- ...
in the 1983 by Walter Gehring's laboratory at the University of Basel, Switzerland, and Thomas Kaufman's laboratory at Indiana University confirmed Lewis's theory.Taubes, GA. Discovering the Homeobox. The Howard Hughes Medical Institute. 2012.


Collinearity

Collinearity is found between the order of the genes on the chromosome and the order in which the genes are expressed along the anteroposterior axis of the embryo. For example, the lab gene is found in the 3' position in the Antennapedia complex, and is expressed in the most anterior head region of the embryo. At the same time, the Abd-B gene is located at the 5' position of the Bithorax complex, and expressed in the most posterior region of the embryo. This suggests that the genes may be activated through a graded process, in which the action is gradually spread along the chromosome. Although the significance of colinearity is still not understood, it is thought to have an important role, due to its conservation in arthropods, and vertebrates including humans.


Para-Segment Individuality

Homeotic selector genes encode regulatory
DNA-binding protein DNA-binding proteins are proteins that have DNA-binding domains and thus have a specific or general affinity for DNA#Base pairing, single- or double-stranded DNA. Sequence-specific DNA-binding proteins generally interact with the major groove ...
s which are all related through a highly conserved DNA binding sequences called the
homeobox 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- ...
(from which the "Hox Complex" name is derived from). Although each all of the DNA-binding complexes are conserved, each para-segment still has an individual identity. The proteins do not bind directly to the DNA, rather, they interact with other regulatory proteins which are already bound to DNA-binding complexes. Different interactions determine which DNA binding sites are recognized and subsequently activated or repressed. Homeotic selector proteins combine in different combinations with regulatory proteins to give each parasegment its identity.


The Hox Complex Carries Positional Information

Certain signals set up the spatial pattern of expression of the Hox complex early in development. The Hox complex acts like a stamp, giving cells in each segment a long term positional value. The cell memory of a given positional value depends on two inputs, the first being the ability of many Hox proteins to autoactivate their own transcription, and the second derived from two large groups of transcriptional regulators: The Polycomb group and the Trithorax group. A defect in either of these regulators results in a pattern which is initially correct but is not maintained at later embryonic stages. The Polycomb and Trithorax regulators act in opposite ways. The Trithorax group maintains Hox transcription after transcription is already activated. The Polycomb group forms stable complexes that bind to the chromatin of Hox genes, and keep it in a repressed state at sites where Hox genes are not active.


Evolutionary Conservation

Homologs of the Homeotic selector gene are found in a variety of species, varying from
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 th ...
ns to
nematode The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-Parasitism, parasitic nematodes also known as eelworms. They are a diverse animal phylum inhab ...
s, to mammals. These genes are grouped similarly to the Hox complex found in insects. The mouse has four complexes, HoxA, HoxB, HoxC, and HoxD, each on different chromosomes. Individual genes in each complex correspond to specific members of the Drosophila genome. The mammalian Hox genes can function 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 species ...
as partial replacements for the Drosophila Hox genes. Each of the four mammalian Hox complexes has a rough counterpart in the insect complex. The theory behind this evolutionary conservation stems from the belief that some common ancestor of worms, flies, and vertebrates had a single primordial homeotic selector gene, an ancestral Hox complex, that went through repeated duplication to form a series of tandem 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 species ...
, this ancestral Hox complex split into two separate complexes: Antennapedia and Bithorax. In mammals, the whole complex repeatedly duplicated resulting in four Hox complexes. This theory has some faults, including that some individual genes have been duplicated while others have been lost.


Arthropod Diversity

Changes in homeotic gene expression contributes to the diversity. The
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 species ...
genome holds its eight homeotic genes in two complexes. The
Invertebrate 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 chordate ...
genome contains 8-10 of is homeotic genes in only one complex, while
Vertebrates 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, ...
have duplicated the Hox complex and have four clusters. Changes in the expression and functionality of individual genes result in various morphology as seen in
arthropod Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a Segmentation (biology), segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and Arth ...
s. The diversity found between the five groups of arthropods is a result of their modular architecture. The arthropods are composed of a series of repeating body segments that can be modified in a limitless number of ways. While some segments may carry antenna, others can be modified to carry wings.
Crustaceans Crustaceans (Crustacea, ) form a large, diverse arthropod taxon which includes such animals as decapods, seed shrimp, branchiopods, fish lice, krill, remipedes, isopods, barnacles, copepods, amphipods and mantis shrimp. The crustacean group ...
have different morphology within the group due to different patterns of Ubx expression in
isopod Isopoda is an order of crustaceans that includes woodlice and their relatives. Isopods live in the sea, in fresh water, or on land. All have rigid, segmented exoskeletons, two pairs of antennae, seven pairs of jointed limbs on the thorax, an ...
s and
brachiopod 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, w ...
s. Similar to brachiopods, isopods have swimming limbs on the second through eighth thoracic segments, however the limbs on the first thoracic segment are smaller than the others, and are used as feeding limbs. The different pattern of Ubx expression correlates with these modifications, possibly a result of an acquired mutation that allows the Ubx enhancers to no longer mediate expression in the first thoracic segment.


Src Expression

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, whi ...
: Src expression is limited to the head region in brachipods and helps in the development of feeding appendages. Ubx is expressed in the thorax where it controls the development of swimming limbs.
Isopod Isopoda is an order of crustaceans that includes woodlice and their relatives. Isopods live in the sea, in fresh water, or on land. All have rigid, segmented exoskeletons, two pairs of antennae, seven pairs of jointed limbs on the thorax, an ...
s: Src expression is detected in both the head and the first thoracic segment (T1) in isopods and as a result, the swimming limb in T1 is transformed into a feeding appendage (the maxillipped). The posterior expansion of Src is possible by the loss of Ubx expression in T1 because Ubx normally represses Src expression.


Dll Expression

Every insect has six legs, one pair found on each of the three thoracic segments while other
arthropod Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a Segmentation (biology), segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and Arth ...
s have a variable number of limbs. This change in morphology is due to functional changes in the Ubx regulatory protein. Ubx and abd-A repress the expression of Distal-less, Dll, a gene responsible for the development of limbs. In the Drosophila embryo, Ubx is expressed at high levels in the
metathorax The metathorax is the posterior of the three segments in the thorax of an insect, and bears the third pair of legs. Its principal sclerites ( exoskeletal plates) are the metanotum (dorsal), the metasternum (ventral), and the metapleuron (lateral) ...
and anterior abdominal segments; abd-A is expressed in the posterior abdominal segments. In combination, these two genes do not allow Dll to function in the first seven abdominal segments. However, Ubx is expressed in the metathorax and does not interfere with the Dll expression because Dll is activated before Ubx is expressed. In crustaceans, there are high levels of both Ubx and DII in all 11 thoracic segments. The expression of DII promotes the development of swimming limbs. The Ubx protein does not repress DII in crustaceans because Ubx is functionally different in insects and crustaceans.


References

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