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Hox gene

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Hox genes are a group of related genes that control the body plan of the embryo along the anterior-posterior (head-tail) axis. After the embryonic segments have formed, the Hox proteins determine the type of segment structures (e.g. legs, antennae, and wings in fruit flies or the different vertebrate ribs in humans) that will form on a given segment. Hox proteins thus confer segmental identity, but do not form the actual segments themselves [1]

Hox genes are defined as having the following properties:

  • their protein product is a transcription factor
  • they contain a DNA sequence known as the homeobox
  • in many animals, the organization of the Hox genes on the chromosome 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.[2]

Hox proteins

The products of Hox genes are Hox proteins. Hox proteins are transcription factors, which are proteins that are capable of binding to specific nucleotide sequences on the DNA called enhancers where they either activate or repress genes. The same Hox 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 Hox gene Antennapedia activates 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.[3] Thus, legs and wings, but not eyes and antennae, will form wherever the Antennapedia protein is located. The ability of Hox proteins to bind DNA is conferred by a part of the protein referred to as the homeodomain. The homeodomain is a 60 amino acid long DNA-binding domain (encoded by its corresponding 180bp DNA sequence, the homeobox). This amino acid sequence folds into a helix-turn-helix motif that is stabilized by a third helix. The consensus polypeptide chain is (typical intron position noted with dashes):[4]

RRRKRTA-YTRYQLLE-LEKEFLF-NRYLTRRRRIELAHSL-NLTERHIKIWFQN-RRMK-WKKEN

Sequence and functional conservation

The homeodomain protein motif is highly conserved across vast evolutionary distances. In addition, homeodomains of individual Hox proteins usually exhibit greater similarity to homeodomains in other species than to proteins encoded by adjacent genes within their own Hox cluster. These two observations led to the suggestions that Hox gene clusters evolved from a single Hox gene via tandem duplication 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.[5]

The functional conservation of Hox proteins can be demonstrated by the fact that a fly can function perfectly well with a chicken Hox protein in place of its own.[6] This means that, despite having a last common ancestor that lived over 670 million years ago,[7] a given Hox protein in chickens and the homologous gene in flies are so similar that they can actually take each other's places.

File:Genes hox.jpg
Hox-gene structures in several phylum

Classification of Hox proteins

Proteins with 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 that). 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, synenty based, and sequence similarity based.[8]

Genes regulated by Hox proteins

Homeobox gene expression in Drosophila melanogaster

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.[9]

Examples of targets
Organism Target gene Normal function of target gene Regulated by
Drosophila distal-less activates gene pathway for limb formation ULTRABITHORAX[10]

(represses distal-less)

distal-less activates gene pathway for limb formation ABDOMINAL-A[10]

(represses distal-less)

decapentaplegic triggers cell shape changes in the gut that are

required for normal visceral morphology

ULTRABITHORAX[11]

(activates decapentaplegic)

reaper Apoptosis: localized cell death creates the segmental

boundary between the maxilla and mandible of the head

DEFORMED[12]

(activates reaper)

dapentaplegic prevents the above cell changes in more posterior

positions

ABDOMINAL-B[11]

(repress decapentaplegic)

Mouse EphA7 Cell adhesion: causes tight association of cells in

distal limb that will form digit, carpal and tarsal bones

HOX-A13[9]

(activates EphA7)

Cdkn1a Cell cycle: differentiation of myelomonocyte cells into

monocytes (white blood cells), with cell cycle arrest

Hox-A10[13]

(activates Cdkn1a)

Enhancer sequences that are bound by homeodomains

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.[14] 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. 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.[15]

However, all homeodomain-containing transcription factors bind essentially the same DNA sequence. The sequence bound by the homeodomain of a Hox protein is only 6 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 begs 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 [16]

Regulation of Hox genes

Just as Hox genes regulate realisator genes, they are in turn regulated themselves by gap genes and pair-rule genes, which are in their turn regulated by maternally-supplied mRNA. 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.[17]

MicroRNA 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.[18]

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 trans (it is transcribed from the HOXC cluster and inhibits late HOXD genes) by binding to Polycomb-group proteins (PRC2).[19]

The chromatin structure is essential for transcription but it also requires the cluster to loop out of the chromosomal territory.[20]

In higher animals including humans, retinoic acid regulates differential expression of Hox genes along the anteroposterior axis.[21] 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.[22]

Colinearity of Hox genes

In some organisms, especially vertebrates, the various Hox genes are situated very close to one another on the chromosome in groups or clusters. Interestingly, 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. The diagram above shows the relationship between the genes and protein expression in flies.

Hox nomenclature

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 are referred to as the HOM-C (for Homeotic Complex). Hox genes (for Homeotic transcription factors) in higher vertebrates are generally arranged in four clusters: Hoxa, Hoxb, Hoxc, and Hoxd. 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.

Human genes

Humans have Hox genes in four clusters:

cluster chromosome genes
HOXA chromosome 7 HOXA1, HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXA10, HOXA11, HOXA13
HOXB chromosome 17 HOXB1, HOXB2, HOXB3, HOXB4, HOXB5, HOXB6, HOXB7, HOXB8, HOXB9, HOXB13
HOXC chromosome 12 HOXC4, HOXC5, HOXC6, HOXC8, HOXC9, HOXC10, HOXC11, HOXC12, HOXC13
HOXD chromosome 2 HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD10, HOXD11, HOXD12, HOXD13

History

Christiane Nüsslein-Volhard 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 Drosophila melanogaster. In the late 1940s, Edward B. Lewis studied the Hox genes, which specify the identity of each segment after they are formed. Incorrect expression of Hox genes can lead to major changes in the morphology of the individual, called homeotic transformations, where one segment develops into the likeness of another. A famous example in Drosophila melanogaster is the mutation of the Ultrabithorax Hox 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 Hox genes.

For their work, Nüsslein-Volhard, Wieschaus, and Lewis were awarded the Nobel Prize in Physiology or Medicine in 1995.

Further information: Nobel foundation website

In 1983, the homeobox was discovered independently by researchers in two labs: Ernst Hafen, Michael Levine, and William McGinnis (in Walter Gehring's lab at the University of Basel, Switzerland) and Matthew P. Scott and Amy Weiner (in Thomas Kaufman's lab at Indiana University in Bloomington).

See also

References

  1. ^ Joseph C. Pearson, Derek Lemons & William McGinnis "Modulating Hox gene functions during animal body patterning" Nature Reviews Genetics 6, 893-904 (December 2005) doi:10.1038/nrg1726
  2. ^ Carroll S. B. (1995). "Homeotic genes and the evolution of arthropods and chordates". Nature. 376 (6540): 479–85. doi:10.1038/376479a0. PMID 7637779. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help)
  3. ^ Cesares and Mann 1998; Plaza et al. 2001
  4. ^ http://www.csb.ki.se/groups/tbu/homeo/consensus.gif
  5. ^ McGinnis W. (1992). "Homeobox genes and axial patterning". Cell. 68 (2): 283–302. doi:10.1016/0092-8674(92)90471-N. PMID 1346368. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ Lutz, B. (1996). "Rescue of Drosophila labial null mutant by the chicken ortholog Hoxb-1 demonstrates that the function of Hox genes is phylogenetically conserved". Genes & Development. 10 (2): 176–184. doi:10.1101/gad.10.2.176. PMID 8566751. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ Ayala, F.J. (20 January 1998). "Origin of the metazoan phyla: Molecular clocks confirm paleontological estimates". Proc. Natl. Acad. Sci. USA. 95 (2): 606–11. doi:10.1073/pnas.95.2.606. PMC 18467. PMID 9435239. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ Hueber S.D. (2010). "Improving Hox Protein Classification across the Major Model Organisms". PLoS ONE. 5 (5): e10820. doi:10.1371/journal.pone.0010820. PMC 2876039. PMID 20520839. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: unflagged free DOI (link)
  9. ^ a b Pearson, JC, Lemons, D. and McGinnis, W. Modulating Hox gene functions during animal body patterning. Nature Rev. Genet. 6, 893–904 (2005).
  10. ^ a b Vachon, G. et al. Homeotic genes of the bithorax complex repress limb development in the abdomen of the Drosophila embryo through the target gene Distal-less. Cell 71, 437–450 (1992).
  11. ^ a b Capovilla, M. & Botas, J. Functional dominance among Hox genes: repression dominates activation in the regulation of dpp. Development 125, 4949–4957 (1998).
  12. ^ Lohmann, I., McGinnis, N., Bodmer, M. & McGinnis, W. The Drosophila Hox gene Deformed sculpts head morphology via direct regulation of the apoptosis activator reaper. Cell 110, 457–466 (2002).
  13. ^ Bromleigh, V. C. & Freedman, L. P. p21 is a transcriptional target of HOXA10 in differentiating myelomonocytic cells. Genes Dev. 14, 2581–2586 (2000).
  14. ^ Gilbert, Developmental Biology, 2006
  15. ^ Hanes and Brent 1989, 1991
  16. ^ Richard S. Mann, Katherine M. Lelli, Rohit Joshi. Chapter 3 Hox Specificity: Unique Roles for Cofactors and Collaborators. Current Topics in Developmental Biology, Volume 88, 2009, Pages 63–101 http://dx.doi.org/10.1016/S0070-2153(09)88003-4
  17. ^ Small S, Blair A, Levine M. 1992. Regulation of even-skipped stripe 2 in the Drosophila embryo. EMBO J. 1992 Nov;11(11):4047-57
  18. ^ Lempradl A, Ringrose L. 2008 How does noncoding transcription regulate Hox genes? Bioessays. 30(2):110-21.
  19. ^ Rinn, JL; Kertesz, M; Wang, JK; Squazzo, SL; Xu, X; Brugmann, SA; Goodnough, LH; Helms, JA; Farnham, PJ (2007). "Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Non-Coding RNAs". Cell. 129 (7): 1311–23. doi:10.1016/j.cell.2007.05.022. PMC 2084369. PMID 17604720.
  20. ^ Fraser, P; Bickmore, W. (2007). "Nuclear organization of the genome and the potential for gene regulation". Nature. 447 (7143): 413–7. doi:10.1038/nature05916. PMID 17522674.
  21. ^ Duester, G (2008). "Retinoic Acid Synthesis and Signaling during Early Organogenesis". Cell. 134 (6): 921–31. doi:10.1016/j.cell.2008.09.002. PMC 2632951. PMID 18805086. {{cite journal}}: Unknown parameter |month= ignored (help)
  22. ^ Montavon; Le Garrec, JF; Kerszberg, M; Duboule, D (2008). "Modeling Hox gene regulation in digits: reverse collinearity and the molecular origin of thumbness". Genes Dev. 22 (3): 346–59. doi:10.1101/gad.1631708. PMC 2216694. PMID 18245448.

Further reading

  • 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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