Homeotic genes specify the anterior-posterior axis and segment identity during early development of metazoan organisms. They are critical for the proper placement and number of embryonic segment structures (such as legs, antennae and eyes).
Homeotic genes are defined by a DNA sequence known as the
homeobox, which is a sequence of 180 nucleotides that codes for a protein domainknown as the homeodomain.
The homeodomain protein motif is highly conserved across vast evolutionary distances. The functional equivalence of homeotic proteins can be demonstrated by the fact that a fly can function perfectly well with a chicken homeotic protein in place of its own [Rescue of Drosophila labial null mutant by the chicken ortholog Hoxb-1 demonstrates that the function of Hox genes is phylogenetically conserved.B Lutz, H C Lu, G Eichele, D Miller, and T C Kaufman. GENES & DEVELOPMENT 10:176-184, 1996 ] . This means that, despite having a last common ancestor that lived over 670 million years ago [Origin of the metazoan phyla: Molecular clocks confirm paleontological estimatesFrancisco José Ayala*, Andrey Rzhetskydagger , and Francisco J. Ayala. Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):606-11.] , a given homeotic protein in chickens and that in flies are so similar that they can actually take each others place.
Although the protein sequence is highly conserved, the DNA sequence from which it is made is slightly less so, a result of
codon degeneracy(i.e., more than one codon codes for the same amino acid). The reason for this high level of conservation is related to the function of these proteins. Homeotic genes set up the basic regional layout of an organism, so that eyes form on the head and not on the abdomen, and limbs form at the sides and not on the head. Even a single mutation in the DNA of these genes can have drastic effects for the organism (see Homeotic Mutants, below), and so these genes have changed relatively little over time.
The protein products of homeotic genes belong to a class of proteins known as
transcription factors, all of which are capable of binding to DNA and thereby regulating the transcription of genes. The homeobox sequence codes for a 60 amino acid helix-turn-helix protein known as the homeodomain. The homeodomain acts as an "on/off" switch for gene transcription by binding to specific sequence enhancers of a gene, which either activates or represses the gene. The same homeotic protein can act as a repressor at one gene and an activator at another. For example, in flies (Drosophila melanogaster) the protein product of the homeotic gene Antennapediaactivates genes that specify the structures of the 2nd thoracic segment, which contains a leg and a wing, and represses genes involved in eye and antenna formation [Cesares and Mann 1998; Plaza et al 2001] . Thus, legs and wings, but not eyes and antennae, will form wherever the Antennapedia protein is located.The genes regulated by homeobox proteins are called realisator genes, and it is the protein products of realisator genes that make tissues, organs and structures (legs, eyes, wings, etc).
Enhancer Sequences That Bind the Homeodomain
The DNA sequence that is bound by the homeodomain protein contains the nucleotide sequence TAAT, with the 5' terminal T being the most important for binding [Gilbert, "Developmental Biology", 2006] . 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 Bicoid, this position is occupied by
lysine, which recognizes and binds to the nucleotide guanine. In Antennapedia, this position is occupied by glutamine, which recognizes and binds to adenine. If the lysine in Bicoid is replaced by glutamine, the resulting protein will recognize Antennapedia-binding enhancer sites [Hanes and Brent 1989, 1991]
Regulation of Hox genes
Just as homeotic genes regulate realisator genes, they are in turn regulated themselves by
gap genesand pair-rule genes, which are in their turn regulated by maternally-supplied mRNA. This results in a transcription factor cascade: maternal turns on gap or pair-rule genes; gap and pair-rule genes turn on homeotic genes; then, finally, homeotic genes turn on 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 [Small S, 1992. Regulation of even-skipped stripe 2 in the Drosophila embryo. EMBO J. 1992 Nov;11(11):4047-57] . MicroRNAstrands located in hox clusters have been shown to inhibit more anterior hox genes ("posterior prevalence phenomenon"), possibly to better fine tune its expression pattern. [ Lempradl A, Ringrose L. 2008 How does noncoding transcription regulate Hox genes? Bioessays. 30(2):110-21.] Non-coding RNA(ncRNA) has been shown to be abundant in Hox clusters. In humans, 231 ncRNA may be present. One of these, HOTAIR, silences in transcription (it is transcribed from the HOXC cluster and inhibits late HOXD genes) by binding to Polycomb-group proteins(PRC2). [Rinn JL et al, 2007. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 129(7):1311-23]
chromatinstructure is essential for transcription but it also requires the cluster to loop out of the chromosomal territory. [ Fraser P, Bickmore W. 2007. Nuclear organization of the genome and the potential for gene regulation. Nature. 447(7143):413-7.]
Quantitative PCR has shown several trends regarding colinearity: the system is in equlibrium and the total number of trascripts depends on the number of genes present according to a linear relationship [ Montavon et al. 2008. Modeling Hox gene regulation in digits: reverse collinearity and the molecular origin of thumbness. Genes Dev. 22(3):346-59] .
Incorrect expression of homeotic genes can lead to major changes in the morphology of the individual. One famous example in the fly
Drosophila melanogasterwas brought about by mutating the Ultrabithoraxhomeotic gene, which specifies the 3rd thoracic segment. Normally, this segment displays a pair of legs and a pair of halteres (a reduced pair of wings used for balancing). In the mutant lacking functional Ultrabithorax protein, the 3rd thoracic segment now expresses the same structures found on the segment to its immediate anterior, the 2nd thoracic segment, which contains a pair of legs and a pair of (fully developed) wings. These mutants sometimes occur in wild populations of flies, and it was these mutants that led to the discovery of homeotic genes.
Colinearity of Homeotic Genes
The various homeotic genes are situated very close to one another on the chromosome in groups or clusters. There is evidence that supports both a linear and a temporal activation of homeotic genes, such that the genes are turned on in order from one end of the chromosome to the other, in the 3' to 5' direction. Anteriorly expressed genes such as "lab" are located at the 3' end of the cluster, while posteriorly expressed genes like "Abd-B" are located at the 5' end [Veronica F. Hinman, Elizabeth K. O'Brien, Gemma S. Richards, Bernard M. Degnan (2003) Expression of anterior Hox genes during larval development of the gastropod Haliotis asininaEvolution & Development 5 (5) , 508–521 doi:10.1046/j.1525-142X.2003.03056.x ] . This relationship between gene order and expression order is known as colinearity.
Classification of Homeotic Genes
Homeotic genes in different phyla have been given different names, which has led to confusion about nomenclature. The complement of homeotic genes of the Ecdysozoa (arthropods,nematodes, etc) is made up of two clusters, the
Antennapediacomplex and the Bithorax complex, which together are referred to as the HOM-C (for Homeotic Complex). Homeotic genes in deuterostomes (echinoderms, chordates) are referred to as Hox genes, and are arranged in four clusters: Hoxa, Hoxb, Hoxc, and Hoxd. Although it is technically incorrect to refer to homeotic genes in non-deuterostome phyla as "hox genes", the practice of using "hox" in place of "homeotic" is now acceptable even in the scientific literature.
Phylogenetic Distribution of Homeotic Genes
Ecdysozoans, there are approximately ten homeotic genes. Vertebrates have four duplicates (paralogues) of these ten genes, known as Hoxa, Hoxb, Hoxc, and Hoxd. These four paralogous clusters are a consequence of the ancestral vertebrate genome being twice duplicated in its entirety [Dehal P, Boore JL (2005) Two Rounds of Whole Genome Duplication in the Ancestral Vertebrate. PLoS Biol 3(10): e314] . The first occurred before the Cnidaria- Bilateriasplit, the second during the evolution of the fishes.
The arrows represent homeotic genes arrayed along a chromosome. The bottom line represents the ten homeotic genes seen in most invertebrates, and is the ancestral complement of the vertebrates. The top four lines represent the four duplicated clusters of these ten genes seen in vertebrates. In order from left to right (anterior to posterior), they are: labial, proboscipedia, zerknullt, Deformed, Sex combs reduced, fushi tarazu,
Antennapedia, Ultrabithorax, Abdominal-A and Abdominal B. Arrows with the same color came from the same ancestral gene.Although these vertebrate genes are duplicates of the same genes seen in the Ecdysozoans, the four copies are not actually identical. Each copy has accumulated its own unique mutations over time, producing proteins with distinct functions. Some have actually been deleted entirely or duplicated again in certain vertebrate groups.For example, Hoxa and Hoxd are involved in the segment identity along the limb axis. Hox expression in the limb has two phases, an early wave of expression for the arm and a late wave for the digits, which involves Hoxd 8 – 13 and has a separate regulatory region 5’ of Hoxd 13 which is not found in teleost fish [Deschamps J. 2007. Ancestral and recently recruited global control of the Hox genes in development. Curr Opin Genet Dev. 17(5):422-7] .
Christiane Nüsslein-Volhard and
Eric F. Wieschausidentified and classified 15 genes of key importance in determining the body plan and the formation of body segments of the fruit fly Drosophila melanogaster. Edward B. Lewisstudied the next step - homeotic genes that govern the development of a larval segment into a specific body segment. Homeotic means that something has been changed into the likeness of something else. Lewis found a collinearity in time and space between the order of the genes in the bithorax complex and their effect regions in the segments.For their work they were awarded the Nobel Prize in Physiology or Medicinein 1995.
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=Homeotic%20gene&rid=dbio.section.1971#2009 The Homeotic Selector Genes] in "Developmental Biology", 6th Edition by Scott F. Gilbert (2000) Published by Sinauer Associates, Inc. ISBN 0-87893-243-7.
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