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The homeobox was discovered independently in 1984 by Ernst Hafen, Michael Levine, and William McGinnis working in the lab of Walter Jakob Gehring at the University of Basel, Switzerland; and by Matthew P. Scott and Amy Weiner, who were then working with Thomas Kaufman at Indiana University in Bloomington. [1][2]  


The existence of genes sharing the homeobox sequence was independently reported by Ernst Hafen, Michael Levine, William McGinnis, and Walter Jakob Gehring of the University of Basel in Switzerland and Matthew P. Scott and Amy Weiner of Indiana University in Bloomington in 1984.



The existence of homeobox genes was first discovered in Drosophila 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 that caused this homeotic phenotype.[3] Analysis of antennapedia revealed that this gene contained a 180 base pair sequence that encoded a DNA binding domain, which Gehring termed the "homeobox".[4] Isolation of homologous genes by Edward de Robertis and Willian McGinnis revealed that numerous genes from a variety of species contained the homeobox.[5][6] Subsequent phylogenetic studies detailing the evolutionary relationship between homeobox-containing genes showed that these genes are present in all bilaterian animals.

Homeobox genes

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Homeobox genes are a super-family of genes that contain the homeobox DNA sequence. Homeobox genes encode homeodomain proteins that act as transcription factors. There are

Regulation

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Homeobox genes are regulated

Colinearity

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Biological function

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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.[7] Many homeodomain proteins induce cellular differentiation 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

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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.[8][9] The regulation of Hox genes is highly complex and involves reciprocal interactions, mostly inhibitory. Drosophila 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.[10]

Mutations

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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.


Types of homeobox genes

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Hox genes

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Hox gene expression in Drosophila melanogaster.
Main article: Hox gene

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.[11] The first vertebrate Hox gene was isolated in Xenopus by Edward De Robertis and colleagues in 1984.[12] 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 cause displacement of body segments during embryonic development. This is called ectopia. 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 and bithorax in Drosophila, which can cause the development of legs instead of antennae and the development of a duplicated thorax, respectively.[13]

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 axis.[14][15] Specific members of the Hox family have been implicated in vascular remodeling, angiogenesis, and disease by orchestrating changes in matrix degradation, integrins, and components of the ECM.[16] HoxA5 is implicated in atherosclerosis.[8][17] HoxD3 and HoxB3 are proinvasive, angiogenic genes that upregulate b3 and a5 integrins and Efna1 in ECs, respectively.[18][19][20][21] 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.[22][23] HoxA5 also upregulates the tumor suppressor p53 and Akt1 by downregulation of PTEN.[24] Suppression of HoxA5 has been shown to attenuate hemangioma growth.[25] HoxA5 has far-reaching effects on gene expression, causing ~300 genes to become upregulated upon its induction in breast cancer cell lines.[25] HoxA5 protein transduction domain overexpression prevents inflammation shown by inhibition of TNFalpha-inducible monocyte binding to HUVECs.[26][27][28]

NKL genes

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LIM genes

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Main article: LIM domain

LIM genes 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, and function in cytoskeletal remodeling, at focal adhesion sites, as scaffolds for protein complexes, and as transcription factors.

Pax genes

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Main article: 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.[29] Pax genes function in embryo segmentation, nervous system development, generation of the eye field, skeletal 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.[30]

POU genes

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Main article: POU family

Proteins containing a POU region consist of a homeodomain and a separate, structurally homologous 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 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 bacteriophages, particularly lambda phage.

POU genes function in

PRD genes

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SINE genes

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