Homeodomain transcription factors
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A homeobox is a
DNA sequence DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. Th ...
, around 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 ...
s 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-grown organism. Homeoboxes are found within
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s that are involved in the regulation of patterns of anatomical development (
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 devel ...
) in
animal Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...
s,
fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
,
plant Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclud ...
s, and numerous single cell
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s. Homeobox genes encode homeodomain
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
products that are
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 fu ...
s sharing a characteristic
protein fold A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similarit ...
structure that binds DNA to regulate expression of target genes. Homeodomain proteins regulate gene expression and cell differentiation during early embryonic development, thus mutations in homeobox genes can cause developmental disorders.
Homeosis In evolutionary developmental biology, homeosis is the transformation of one organ into another, arising from mutation in or misexpression of certain developmentally critical genes, specifically homeotic genes. In animals, these developmental gen ...
is a term coined 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 ...
to describe the outright replacement of a discrete body part with another body part, e.g.
antennapedia ''Antennapedia'' (abbreviated ''Antp'') is a Hox gene first discovered in ''Drosophila'' which controls the formation of insect leg, legs during development. Loss-of-function mutations in the regulatory region of this gene result in the devel ...
—replacement of the antenna on the head of a fruit fly with legs. The "homeo-" prefix in the words "homeobox" and "homeodomain" stems from this mutational phenotype, which is observed when some of these genes are mutated in
animals 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 ...
. The homeobox domain was first identified in a number of ''Drosophila''
homeotic In evolutionary developmental biology, homeosis is the transformation of one organ into another, arising from mutation in or misexpression of certain developmentally critical genes, specifically homeotic genes. In animals, these developmental gene ...
and segmentation proteins, but is now known to be well-conserved in many other animals, including
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, ...
s.


Discovery

The existence of homeobox genes was first discovered 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 ...
'' by isolating the gene responsible for a homeotic transformation where legs grow from the head instead of the expected antennae. Walter Gehring identified a gene called ''
antennapedia ''Antennapedia'' (abbreviated ''Antp'') is a Hox gene first discovered in ''Drosophila'' which controls the formation of insect leg, legs during development. Loss-of-function mutations in the regulatory region of this gene result in the devel ...
'' that caused this homeotic phenotype. Analysis of ''antennapedia'' revealed that this gene contained a 180 base pair sequence that encoded a DNA binding domain, which William McGinnis termed the "homeobox". The existence of additional ''Drosophila'' genes containing the ''antennapedia'' homeobox sequence was independently reported by Ernst Hafen, Michael Levine,
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 ...
, and
Walter Jakob 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 ...
of 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 ...
in
Switzerland ). Swiss law does not designate a ''capital'' as such, but the federal parliament and government are installed in Bern, while other federal institutions, such as the federal courts, are in other cities (Bellinzona, Lausanne, Luzern, Neuchâtel ...
and
Matthew P. Scott Matthew P. Scott is an American biologist who was the tenth president of the Carnegie Institution for Science. While at Stanford University, Scott studied how embryonic and later development is governed by proteins that control gene activity and c ...
and Amy Weiner of Indiana University in Bloomington in 1984. Isolation of homologous genes by Edward de Robertis and William McGinnis revealed that numerous genes from a variety of species contained the homeobox. Subsequent phylogenetic studies detailing the evolutionary relationship between homeobox-containing genes showed that these genes are present in all bilaterian animals.


Homeodomain structure

The characteristic homeodomain
protein fold A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similarit ...
consists of a 60- amino acid long domain composed of three alpha helixes. The following shows the consensus homeodomain (~60 amino acid chain):
            Helix 1          Helix 2         Helix 3/4
         ______________    __________    _________________
RRRKRTAYTRYQLLELEKEFHFNRYLTRRRRIELAHSLNLTERHIKIWFQNRRMKWKKEN
...., ...., ...., ...., ...., ...., ...., ...., ...., ...., ...., ...., 
         10        20        30        40        50        60
Helix 2 and helix 3 form a so-called helix-turn-helix (HTH) structure, where the two alpha helices are connected by a short loop region. The
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
two helices of the homeodomain are antiparallel and the longer C-terminal helix is roughly perpendicular to the axes established by the first two. It is this third helix that interacts directly with DNA via a number of hydrogen bonds and hydrophobic interactions, as well as indirect interactions via water molecules, which occur between specific side chains and the exposed bases within the
major groove Major (commandant in certain jurisdictions) is a military rank of commissioned officer status, with corresponding ranks existing in many military forces throughout the world. When used unhyphenated and in conjunction with no other indicators ...
of the DNA. Homeodomain proteins are found in
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s. Through the HTH motif, they share limited sequence similarity and structural similarity to prokaryotic transcription factors, such as lambda phage proteins that alter the expression of genes in prokaryotes. The HTH motif shows some sequence similarity but a similar structure in a wide range of DNA-binding proteins (e.g., cro and
repressor protein In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
s, homeodomain proteins, etc.). One of the principal differences between HTH motifs in these different proteins arises from the stereochemical requirement for glycine in the turn which is needed to avoid
steric Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...
interference of the beta-carbon with the main chain: for cro and repressor proteins the glycine appears to be mandatory, whereas for many of the homeotic and other DNA-binding proteins the requirement is relaxed.


Sequence specificity

Homeodomains can bind both specifically and nonspecifically to B-DNA with the C-terminal recognition helix aligning in the DNA's major groove and the unstructured peptide "tail" at the N-terminus aligning in the minor groove. The recognition helix and the inter-helix loops are rich in
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
and
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
residues, which form
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
s to the DNA backbone. Conserved hydrophobic residues in the center of the recognition helix aid in stabilizing the helix packing. Homeodomain proteins show a preference for the DNA sequence 5'-TAAT-3'; sequence-independent binding occurs with significantly lower affinity. The specificity of a single homeodomain protein is usually not enough to recognize specific target gene promoters, making cofactor binding an important mechanism for controlling binding sequence specificity and target gene expression. To achieve higher target specificity, homeodomain proteins form complexes with other transcription factors to recognize the promoter region of a specific target gene.


Biological function

Homeodomain proteins function as transcription factors due to the DNA binding properties of the conserved HTH motif. Homeodomain proteins are considered to be master control genes, meaning that a single protein can regulate expression of many target genes. Homeodomain proteins direct the formation of the body axes and body structures during early embryonic development. Many homeodomain proteins induce
cellular differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...
by initiating the cascades of coregulated genes required to produce individual tissues and organs. Other proteins in the family, such as NANOG are involved in maintaining pluripotency and preventing cell differentiation.


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. The regulation of Hox genes is highly complex and involves reciprocal interactions, mostly inhibitory.
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 ...
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.


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, ''
Lokiarchaeum Lokiarchaeota is a proposed phylum of the Archaea. The phylum includes all members of the group previously named Deep Sea Archaeal Group (DSAG), also known as Marine Benthic Group B (MBG-B). Lokiarchaeota is part of the superphylum Asgard (archa ...
'', that is regarded as the prokaryote closest to the ancestor of all eukaryotes. 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. Molecular evidence shows that some limited number of Hox genes have existed in the Cnidaria since before the earliest true
Bilatera The Bilateria or bilaterians are animals with bilateral symmetry as an embryo, i.e. having a left and a right side that are mirror images of each other. This also means they have a head and a tail (anterior-posterior axis) as well as a belly and ...
, making these genes pre- Paleozoic. 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. Gene duplication followed by neofunctionalization is responsible for the many homeobox genes found in eukaryotes. Comparison of homeobox genes and gene clusters has been used to understand the evolution of genome structure and body morphology throughout metazoans.


Types of homeobox genes


Hox genes

Hox genes are the most commonly known subset of homeobox genes. They are essential metazoan genes that determine the identity of embryonic regions along the anterior-posterior axis. The first vertebrate Hox gene was isolated in '' Xenopus'' by Edward De Robertis and colleagues in 1984. The main interest in this set of genes stems from their unique behavior and arrangement in the genome. Hox genes are typically found in an organized cluster. The linear order of Hox genes within a cluster is directly correlated to the order they are expressed in both time and space during development. This phenomenon is called colinearity. Mutations in these
homeotic genes 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 factors, transc ...
cause displacement of body segments during embryonic development. This is called
ectopia Ectopia, ectopic, or ectopy may refer to: *Ectopia (medicine), including a list of medical uses of ectopia or ectopic **Ectopic pregnancy, a pregnancy that occurs outside the uterus **Ectopic beat, or cardiac ectopy, a disturbance in cardiac rhyt ...
. 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 ''Antennapedia'' (abbreviated ''Antp'') is a Hox gene first discovered in ''Drosophila'' which controls the formation of insect leg, legs during development. Loss-of-function mutations in the regulatory region of this gene result in the devel ...
'' and
bithorax 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 ...
in ''Drosophila'', which can cause the development of legs instead of antennae and the development of a duplicated thorax, respectively. In vertebrates, the four paralog clusters are partially redundant in function, but have also acquired several derived functions. For example, HoxA and HoxD specify segment identity along the
limb Limb may refer to: Science and technology *Limb (anatomy), an appendage of a human or animal *Limb, a large or main branch of a tree *Limb, in astronomy, the curved edge of the apparent disk of a celestial body, e.g. lunar limb *Limb, in botany, ...
axis. Specific members of the Hox family have been implicated in vascular remodeling,
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
, and disease by orchestrating changes in matrix degradation, integrins, and components of the ECM. HoxA5 is implicated in atherosclerosis. HoxD3 and HoxB3 are proinvasive, angiogenic genes that upregulate b3 and a5 integrins and Efna1 in ECs, respectively. HoxA3 induces endothelial cell (EC) migration by upregulating MMP14 and uPAR. Conversely, HoxD10 and HoxA5 have the opposite effect of suppressing EC migration and angiogenesis, and stabilizing adherens junctions by upregulating TIMP1/downregulating uPAR and MMP14, and by upregulating Tsp2/downregulating VEGFR2, Efna1, Hif1alpha and COX-2, respectively. HoxA5 also upregulates the tumor suppressor p53 and Akt1 by downregulation of PTEN. Suppression of HoxA5 has been shown to attenuate hemangioma growth. HoxA5 has far-reaching effects on gene expression, causing ~300 genes to become upregulated upon its induction in breast cancer cell lines. HoxA5 protein transduction domain overexpression prevents inflammation shown by inhibition of TNFalpha-inducible monocyte binding to HUVECs.


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.


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. Pax genes function in embryo segmentation, nervous system development, generation of the
frontal eye fields The frontal eye fields (FEF) are a region located in the frontal cortex, more specifically in Brodmann area 8 or BA8, of the primate brain. In humans, it can be more accurately said to lie in a region around the intersection of the middle fronta ...
,
skeletal A skeleton is the structural frame that supports the body of an animal. There are several types of skeletons, including the exoskeleton, which is the stable outer shell of an organism, the endoskeleton, which forms the support structure inside ...
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.


POU genes

Proteins containing a POU region consist of a homeodomain and a separate,
structurally homologous A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similarit ...
POU domain that contains two helix-turn-helix motifs and also binds DNA. The two domains are linked by a flexible loop that is long enough to stretch around the DNA helix, allowing the two domains to bind on opposite sides of the target DNA, collectively covering an eight-base segment with
consensus sequence In molecular biology and bioinformatics, the consensus sequence (or canonical sequence) is the calculated order of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment. It serves as a simplified r ...
5'-ATGCAAAT-3'. The individual domains of POU proteins bind DNA only weakly, but have strong sequence-specific affinity when linked. The POU domain itself has significant structural similarity with repressors expressed in
bacteriophage A bacteriophage (), also known informally as a ''phage'' (), is a duplodnaviria virus that infects and replicates within bacteria and archaea. The term was derived from "bacteria" and the Greek φαγεῖν ('), meaning "to devour". Bacteri ...
s, particularly lambda phage.


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. Conservation of codomains suggests a common eukaryotic ancestry for TALE and non-TALE homeodomain proteins.


Human homeobox genes

The Hox genes in humans are organized in four chromosomal clusters: ParaHox genes are analogously found in four areas. They include CDX1, CDX2, CDX4; GSX1,
GSX2 GSX may refer to: * Gsx (gene family) * GSX Techedu, a large Chinese online tutoring company * Asurada GSX, a fictional racing car from ''Future GPX Cyber Formula'' * Buick GSX, a muscle car * Gandhi Smarak Road railway station, in Maharashtra, Ind ...
; and PDX1. Other genes considered Hox-like include
EVX1 Evx1 is a mammalian gene located downstream of the HoxA cluster, which encodes for a homeobox transcription factor. Evx1 is a homolog of even-skipped (eve), which is a pair-rule gene that regulates body segmentation in Drosophila. The expression ...
,
EVX2 V Cars. LLC, called Visionary Vehicles prior to mid-2008, was an international automobile import and distribution company, founded by Malcolm Bricklin and engaging in the development and sale of Chinese-made motor vehicles in North America. The c ...
; GBX1,
GBX2 Homeobox protein GBX-2 is a protein that in humans is encoded by the ''GBX2'' gene. Summary Gastrulation Brain Homeobox 2, or commonly known as GBX2, is a type of transcription factor that aids in the arranging of the midbrain and hindbrain du ...
;
MEOX1 Homeobox protein MOX-1 is a protein that in humans is encoded by the ''MEOX1'' gene. Function This gene encodes a member of a subfamily of non-clustered, diverged, antennapedia-like homeobox-containing genes. The encoded protein may play a rol ...
, MEOX2; and
MNX1 Motor neuron and pancreas homeobox 1 (MNX1), also known as Homeobox HB9 (HLXB9), is a human protein encoded by the ''MNX1'' gene. Clinical significance Mutations in the ''MNX1'' gene are associated with Currarino syndrome Currarino syndrome ...
. The NK-like (NKL) genes, some of which are considered "MetaHox", are grouped with Hox-like genes into a large ANTP-like group. Humans have a "distal-less homeobox" family: DLX1,
DLX2 Homeobox protein DLX-2 is a protein that in humans is encoded by the ''DLX2'' gene. Many vertebrate homeo box-containing genes have been identified on the basis of their sequence similarity with Drosophila developmental genes. Members of the Dlx ...
, DLX3,
DLX4 Homeobox protein DLX-4 is a protein that in humans is encoded by the ''DLX4'' gene. Function Many vertebrate homeobox-containing genes have been identified on the basis of their sequence similarity with ''Drosophila'' developmental genes. Memb ...
, DLX5, and DLX6. Dlx genes are involved in the development of the nervous system and of limbs. They are considered a subset of the NK-like genes. Human TALE (Three Amino acid Loop Extension) homeobox genes for an "atypical" homeodomain consist of 63 rather than 60 amino acids: IRX1, IRX2,
IRX3 Iroquois-class homeodomain protein IRX-3, also known as Iroquois homeobox protein 3, is a protein that in humans is encoded by the ''IRX3'' gene. Discovery and name The Iroquois family of genes was discovered in ''Drosophila'' during a mutagen ...
,
IRX4 Iroquois-class homeodomain protein IRX-4, also known as Iroquois homeobox protein 4, is a protein that in humans is encoded by the ''IRX4'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the ...
, IRX5,
IRX6 Iroquois-class homeodomain protein IRX-6, also known as Iroquois homeobox protein 6, is a protein that in humans is encoded by the ''IRX6'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the ...
; MEIS1, MEIS2, MEIS3; MKX; PBX1,
PBX2 Pre-B-cell leukemia transcription factor 2 is a protein that in humans is encoded by the ''PBX2'' gene. Function This gene encodes a ubiquitously expressed member of the TALE/PBX homeobox family. It was identified by its similarity to a homeob ...
,
PBX3 Pre-B-cell leukemia transcription factor 3 is a protein that in humans is encoded by the ''PBX3'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ...
, PBX4; PKNOX1, PKNOX2;
TGIF1 Homeobox protein TGIF1 is a protein that, in humans, is encoded by the ''TGIF1'' gene. Alternative splicing has been observed at this locus and eight variants, encoding four distinct isoforms, are described. Function The protein encoded by thi ...
,
TGIF2 Homeobox protein TGIF2 is a protein that in humans is encoded by the ''TGIF2'' gene. The protein encoded by this gene is a DNA-binding homeobox protein and a transcriptional repressor. The encoded protein appears to repress transcription by recr ...
,
TGIF2LX TGIF may refer to: * Thank God It's Friday (disambiguation), a common expression. Arts and media * TGIF (TV programming block), a former two-hour programming block on the American television network ABC * "Last Friday Night (T.G.I.F.)", a 2011 ...
,
TGIF2LY TGIF may refer to: * Thank God It's Friday (disambiguation), a common expression. Arts and media * TGIF (TV programming block), a former two-hour programming block on the American television network ABC * "Last Friday Night (T.G.I.F.)", a 2011 s ...
. In addition, humans have the following homeobox genes and proteins: * LIM-class:
ISL1 Insulin gene enhancer protein ISL-1 is a protein that in humans is encoded by the ''ISL1'' gene. Function This gene encodes a transcription factor containing two N-terminal LIM domains and one C-terminal homeodomain. The encoded protein play ...
,
ISL2 Isl (or isl) is a common abbreviation for "island" or "islands". ISL may also refer to: Education and research * Illinois Security Lab, a research laboratory at the University of Illinois at Urbana-Champaign * Independent School League (disambi ...
; LHX1, LHX2,
LHX3 LIM/homeobox protein Lhx3 is a protein that in humans is encoded by the ''LHX3'' gene. Function ''LHX3'' encodes a protein of a large protein family, members of which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encode ...
,
LHX4 LIM/homeobox protein Lhx4 is a protein that in humans is encoded by the ''LHX4'' gene. This gene encodes a member of a large protein family which contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein may functio ...
, LHX5,
LHX6 LIM/homeobox protein Lhx6 is a protein that in humans is encoded by the ''LHX6'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ...
, LHX8, LHX9; LMX1A, LMX1B * POU-class: HDX;
POU1F1 POU domain, class 1, transcription factor 1 (Pit1, growth hormone factor 1), also known as POU1F1, is a transcription factor for growth hormone. Function PIT1 is a pituitary-specific transcription factor responsible for pituitary development a ...
;
POU2F1 POU domain, class 2, transcription factor 1 is a protein that in humans is encoded by the ''POU2F1'' gene. Interactions POU2F1 has been shown to interact with: * EPRS, * Glucocorticoid receptor, * Glyceraldehyde 3-phosphate dehydrogenase, ...
;
POU2F2 POU or pou may refer to: People * Pou (surname), a surname * Chu Pou (303–350), Chinese general and politician * Pou Temara (born 1948), New Zealand Māori academic Codes * POU, IATA airport code and FAA location identifier for Hudson Valley Re ...
;
POU2F3 POU domain, class 2, transcription factor 3 is a protein that in humans is encoded by the ''POU2F3'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meanin ...
; POU3F1; POU3F2;
POU3F3 POU class 3 homeobox 3 is a protein that in humans is encoded by the POU3F3 gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''bir ...
;
POU3F4 POU domain, class 3, transcription factor 4 is a protein that in humans is encoded by the ''POU3F4'' gene found on the X chromosome. POU3F4 is involved in the patterning of the neural tube and both the paraventricular and supraoptic nuclei of t ...
;
POU4F1 POU domain, class 4, transcription factor 1 (POU4F1) also known as brain-specific homeobox/POU domain protein 3A (BRN3A), homeobox/POU domain protein RDC-1 or Oct-T1 is a protein that in humans is encoded by the ''POU4F1'' gene. BRN3A (POU4F1) is ...
; POU4F2;
POU4F3 POU domain, class 4, transcription factor 3 is a protein that in humans is encoded by the ''POU4F3'' gene. It's a member of BRN-3 group, also known as POU family class 4. Nomenclature DFNA15 refers to a type of nonsyndromic deafness Nonsyndrom ...
; POU5F1; POU5F1P1; POU5F1P4; POU5F2; POU6F1; and POU6F2 * CERS-class:
LASS2 Ceramide synthase 2, also known as LAG1 longevity assurance homolog 2 or Tumor metastasis-suppressor gene 1 protein is an enzyme that in humans is encoded by the CERS2 gene. Ceramide synthase 2 is a ceramide synthase that catalyses the synthes ...
, LASS3, LASS4, LASS5, LASS6; * HNF-class:
HMBOX1 Homeobox containing 1, also known as homeobox telomere-binding protein 1 (HOT1), is a protein that in humans is encoded by the HMBOX1 gene. HMBOX1 directly binds to the double-stranded repeat sequence of telomeres. HMBOX1 has originally been ide ...
; HNF1A,
HNF1B HNF1 homeobox B (hepatocyte nuclear factor 1 homeobox B), also known as HNF1B or transcription factor 2 (TCF2), is a human gene. Function HNF1B encodes hepatocyte nuclear factor 1-beta, a protein of the homeobox-containing basic helix-turn-hel ...
; * SINE-class: SIX1,
SIX2 Homeobox protein SIX2 is a protein that in humans is encoded by the ''SIX2'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''b ...
, SIX3,
SIX4 Homeobox protein SIX4 is a protein that in humans is encoded by the ''SIX4'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''b ...
, SIX5, SIX6 * CUT-class:
ONECUT1 One cut homeobox 1 is a protein that in humans is encoded by the ONECUT1 gene. Function This gene encodes a member of the Cut homeobox family of transcription factors. Expression of the encoded protein is enriched in the liver, where it stimul ...
, ONECUT2, ONECUT3;
CUX1 CUX1 is an animal gene. The name stands for Cut like homeobox 1. The term "cut" derives from the "cut wing" phenotype observed in a mutant of ''Drosophila melanogaster''. In mammals, a CCAAT-displacement activity was originally described in DNA bind ...
, CUX2; SATB1, SATB2; * ZF-class: ADNP,
ADNP2 ADNP may refer to: *Arab Democratic Nasserist Party, a political party in Egypt *ADNP (gene) Activity-dependent neuroprotector homeobox is a protein that in humans is encoded by the ADNP gene. Function Vasoactive intestinal peptide is a neurop ...
;
TSHZ1 Teashirt zinc finger homeobox 1 is a protein that in humans is encoded by the TSHZ1 gene. Function This gene encodes a colon cancer antigen that was defined by serological analysis of recombinant cDNA expression libraries. The encoded protein ...
, TSHZ2, TSHZ3; ZEB1, ZEB2;
ZFHX2 Zinc finger homeobox 2 is a protein that in humans is encoded by the ZFHX2 gene. It has been implicated in pain insensitivity Hereditary sensory and autonomic neuropathy (HSAN) or hereditary sensory neuropathy (HSN) is a condition used to desc ...
,
ZFHX3 Zinc finger homeobox protein 3 is a protein that in humans is encoded by the ''ZFHX3'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generatio ...
, ZFHX4;
ZHX1 Zinc fingers and homeoboxes protein 1 is a protein that in humans is encoded by the ''ZHX1'' gene. The members of the zinc fingers and homeoboxes gene family are nuclear homodimeric transcriptional repressors that interact with the A subunit of ...
, HOMEZ; * PRD-class: ALX1 (CART1),
ALX3 The ALX3 gene, also known as aristaless-like homeobox 3, is a protein coding gene that provides instructions to build a protein which is a member of the homeobox protein family. This grouping regulates patterns of anatomical development. The gen ...
, ALX4; ARGFX; ARX; DMBX1; DPRX; DRGX; DUXA, DUXB, DUX ( 1, 2, 3, 4, 4c, 5);
ESX1 Homeobox protein ESX1 is a protein that in humans is encoded by the ''ESX1'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''bi ...
; GSC, GSC2; HESX1;
HOPX Homeodomain-only protein is a protein that in humans is encoded by the ''HOPX'' gene. It is an important regulator of cardiac development and a marker of hippocampal neural stem cells. Function The protein encoded by this gene is a homeodomai ...
;
ISX The Iraq Stock Exchange (ISX), formerly the Baghdad Stock Exchange, is a stock exchange in Baghdad, Iraq. It was established by the Coalition Provisional Authority (CPA) Order No. 74 as a ''sui generis'' independent non-profit organization on Apr ...
; LEUTX; MIXL1;
NOBOX Homeobox protein NOBOX, also known as newborn ovary homeobox protein, is a protein that in humans is encoded by the ''NOBOX'' gene. The official symbol (NOBOX) and the official full name (NOBOX oogenesis homeobox) are maintained by the HGNC. The ' ...
; OTP; OTX1, OTX2, CRX;
PAX2 Paired box gene 2, also known as Pax-2, is a protein which in humans is encoded by the ''PAX2'' gene. Function The Pax Genes, or Paired-Box Containing Genes, play important roles in the development and proliferation of multiple cell lines, dev ...
, PAX3, PAX4,
PAX5 Paired box protein Pax-5 is a protein that in humans is encoded by the ''PAX5'' gene. Function The PAX5 gene is a member of the paired box (PAX) family of transcription factors. The central feature of this gene family is a novel, highly cons ...
, PAX6, PAX7, PAX8; PHOX2A, PHOX2B;
PITX1 Paired-like homeodomain 1 is a protein that in humans is encoded by the ''PITX1'' gene. Function This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family are invo ...
, PITX2, PITX3; PROP1;
PRRX1 Paired related homeobox 1 is a protein that in humans is encoded by the ''PRRX1'' gene. Function The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein funct ...
,
PRRX2 Paired mesoderm homeobox protein 2 is a protein that in humans is encoded by the ''PRRX2'' gene. Function The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins. Expression is localized to prolife ...
;
RAX The Rax is a mountain range in the Northern Limestone Alps on the border of the Austrian federal provinces of Lower Austria and Styria. Its highest peak is the ''Heukuppe'' (2,007 m). The Rax, together with the nearby Schneeberg, are a tradition ...
,
RAX2 The Rax is a mountain range in the Northern Limestone Alps on the border of the Austrian federal provinces of Lower Austria and Styria. Its highest peak is the ''Heukuppe'' (2,007 m). The Rax, together with the nearby Schneeberg, are a traditio ...
;
RHOXF1 Rhox homeobox family member 1 is a protein that in humans is encoded by the ''RHOXF1'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation ...
,
RHOXF2 Rhox homeobox family, member 2 also known as paired-like homeobox protein (PEPP-2) is a protein in humans that is encoded by the RHOXF2 gene. RHOXF2 contains a glutamine-rich N-terminus, a homeodomain, and a proline-rich C-terminus The C-termin ...
/ 2B; SEBOX; SHOX,
SHOX2 Short-stature homeobox 2, also known as homeobox protein Og12X or paired-related homeobox protein SHOT, is a protein that in humans is encoded by the ''SHOX2'' gene. Function SHOX2 is a member of the homeobox family of genes that encode protei ...
; TPRX1; UNCX;
VSX1 Visual system homeobox 1 is a protein that in humans is encoded by the ''VSX1'' gene. The protein encoded by this gene contains a paired-like homeodomain and binds to the core of the locus control region of the red/green cone opsin gene cluster. ...
,
VSX2 Visual system homeobox 2 is a protein that in humans is encoded by the ''VSX2'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ' ...
* NKL-class: BARHL1,
BARHL2 BarH-like homeobox 2 is a protein in humans that is encoded by the BARHL2 gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''bi ...
; BARX1,
BARX2 Barx (, es, Bárig) is a municipality in the ''comarca'' of Safor in the Valencian Community, Spain. Etymology Tackling the etymology of the place name "Barx" is no simple matter and has caused heated controversy between scholars of Roman and ...
; BSX; DBX1,
DBX2 Homeobox protein DBX2, also known as developing brain homeobox protein 2, is a protein that in humans is encoded by the ''DBX2'' gene. DBX2 plays an important role in the development of the central nervous system, specifically in the development o ...
;
EMX1 Homeobox protein EMX1 is a protein that in humans is encoded by the ''EMX1'' gene. The transcribed EMX1 gene is a member of the EMX family of transcription factors. The EMX1 gene, along with its family members, are expressed in the developing cer ...
,
EMX2 Homeobox protein Emx2 is a protein that in humans is encoded by the ''EMX2'' gene. Function The homeodomain transcription factor EMX2 is critical for central nervous system and urogenital development. EMX1 (MIM 600034) and EMX2 are related to t ...
; EN1, EN2; HHEX; HLX1;
LBX1 Transcription factor LBX1 is a protein that in humans is encoded by the ''LBX1'' gene. This gene and the orthologous mouse gene were found by their homology to the Drosophila lady bird early and late homeobox genes. In the mouse, this gene is a ...
,
LBX2 In computing, LBX, or Low Bandwidth X, is a protocol to use the X Window System over network links with low bandwidth and high latency. It was introduced in X11R6.3 ("Broadway") in 1996, but never achieved wide use. It was disabled by default as ...
; MSX1, MSX2; NANOG; NOTO; TLX1,
TLX2 T-cell leukemia homeobox protein 2 is a protein that in humans is encoded by the ''TLX2'' gene. Interactions TLX2 has been shown to interact with YWHAH 14-3-3 protein eta also referred to as 14-3-3η is a protein that in humans is encoded by ...
,
TLX3 T-cell leukemia homeobox protein 3 is a protein that in humans is encoded by the ''TLX3'' gene. RNX (HOX11L2, TLX3) belongs to a family of orphan homeobox genes that encode DNA-binding nuclear transcription factors. Members of the HOX11 gene fa ...
;
TSHZ1 Teashirt zinc finger homeobox 1 is a protein that in humans is encoded by the TSHZ1 gene. Function This gene encodes a colon cancer antigen that was defined by serological analysis of recombinant cDNA expression libraries. The encoded protein ...
, TSHZ2, TSHZ3; VAX1,
VAX2 VAX (an acronym for Virtual Address eXtension) is a series of computers featuring a 32-bit computing, 32-bit instruction set architecture (ISA) and virtual memory that was developed and sold by Digital Equipment Corporation (DEC) in the late 20 ...
, VENTX; ** Nkx: NKX2-1,
NKX2-4 Marine Corps Air Station Miramar (MCAS Miramar) , formerly Naval Auxiliary Air Station (NAAS) Miramar and Naval Air Station (NAS) Miramar, is a United States Marine Corps installation that is home to the 3rd Marine Aircraft Wing, which is the av ...
;
NKX2-2 Homeobox protein Nkx-2.2 is a protein that in humans is encoded by the ''NKX2-2'' gene. Homeobox protein Nkx-2.2 contains a homeobox domain and may be involved in the morphogenesis of the central nervous system. This gene is found on chromosome ...
,
NKX2-8 Marine Corps Air Station Miramar (MCAS Miramar) , formerly Naval Auxiliary Air Station (NAAS) Miramar and Naval Air Station (NAS) Miramar, is a United States Marine Corps installation that is home to the 3rd Marine Aircraft Wing, which is the av ...
; NKX3-1, NKX3-2;
NKX2-3 Homeobox protein Nkx-2.3 is a protein that in humans is encoded by the ''NKX2-3'' gene. NKX2C is a member of the NKX family of homeodomain-containing transcription factor In molecular biology, a transcription factor (TF) (or sequence-specifi ...
, NKX2-5, NKX2-6; HMX1,
HMX2 HMX, also called octogen, is a powerful and relatively insensitive nitroamine high explosive, chemically related to RDX. Like RDX, the compound's name is the subject of much speculation, having been variously listed as High Melting Explosive, Her ...
, HMX3;
NKX6-1 Homeobox protein Nkx-6.1 is a protein that in humans is encoded by the ''NKX6-1'' gene. Function In the pancreas, NKX6.1 is required for the development of beta cell Beta cells (β-cells) are a type of cell found in pancreatic islets that ...
;
NKX6-2 Homeobox protein Nkx-6.2 is a protein that in humans is encoded by the ''NKX6-2'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' o ...
; NKX6-3;


See also

*
Evolutionary developmental biology Evolutionary developmental biology (informally, evo-devo) is a field of biological research that compares the developmental processes of different organisms to infer how developmental processes evolved. The field grew from 19th-century beginni ...
* Body plan


References


Further reading

* * *


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.
* * {{genarch Genes Developmental genetics Protein domains Transcription factors Evolutionary developmental biology