In most bilateral animals, the Hox-cluster genes encode a group of conserved transcription factors that are responsible for defining axial identity on the anterior–posterior (A–P) axis. They do this by activating or repressing genes in a variety of tissues throughout development.
Hox proteins directly regulate high-level 'executive' genes such as transcription factors and intercellular signaling molecules, as well as 'realizator' genes that affect cell adhesion, number, shape and growth.
The ability of different Hox proteins to select specific target enhancers is partly attributable to cooperative binding with Extradenticle (EXD)–PBX (Pre-B-cell homeobox) and Homothorax (HTH)–MEIS proteins. On other targets, Hox proteins act through monomer binding sites, with the aid of other unknown cofactors. Teashirt and Disco are good candidates for additional Hox cofactors.
Hox-response elements often possess EXD-binding and HTH-binding sites in addition to Hox-protein-binding sites, but otherwise they have little in common, showing great variation in size, conservation and number of Hox sites required for proper function.
In silico searches for new direct Hox-regulated enhancers have so far been unsuccessful, indicating that we still only have a primitive understanding of Hox-dependent transcriptional regulation.
The evolution of Hox gene expression patterns and protein sequences has probably contributed significantly to the current morphological diversity that is seen in bilateria.
The expression patterns of Hox proteins might be modulated by several well-conserved microRNAs, including miR-10, miR-iab-4 and miR-196, which are expressed in Hox-like patterns along the A–P axis of animal embryos.
With their power to shape animal morphology, few genes have captured the imagination of biologists as the evolutionarily conserved members of the Hox clusters have done. Recent research has provided new insight into how Hox proteins cause morphological diversity at the organismal and evolutionary levels. Furthermore, an expanding collection of sequences that are directly regulated by Hox proteins provides information on the specificity of target-gene activation, which might allow the successful prediction of novel Hox-response genes. Finally, the recent discovery of microRNA genes within the Hox gene clusters indicates yet another level of control by Hox genes in development and evolution.
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We thank the National Institutes of Health (NIH) and the National Science Foundation (NSF) for funding support, and our colleagues in the Hox and microRNA fields for illuminating conversations.
The authors declare no competing financial interests.
- HOMEOTIC TRANSFORMATION
The transformation of one body region into the likeness of another.
A phylogenetic subdivision of animals that is characterized by left–right symmetry along the primary body axis at some stage of the life cycle.
- ORAL–ABORAL AXIS
The body axis from the mouth to the body surface opposite the mouth, commonly used in animals that have no obvious bilateral symmetry.
Genes in the same organism that have evolved from a gene duplication, usually with a subsequent, sometimes subtle, divergence of function.
Each of seven neuroepithelial segments found in the embryonic hindbrain that adopt distinct molecular and cellular properties, restrictions in cell mixing, and ordered domains of gene expression.
A web based application for generating sequence logos — graphical representations of an amino-acid or nucleic-acid motif weight matrix.
Small, non-coding RNAs that are components of a large protein complex (RISC) and are involved in repression of protein production from mRNAs that contain sequences with significant complementarity to the microRNA.
- VISCERAL MESODERM
A subset of mesodermal cells that surround endodermal tissues such as the gut, also known as splanchnic mesoderm.
Distal limb primordia that give rise to structures such as the mouse paw.
- COS7 CELLS
A commonly used fibroblast-like cell line that is derived from African green monkey kidneys.
- MYELOMONOCYTIC CELLS
Pluripotent cells that differentiate into immune cells such as granulocytes, dendritic cells and monocytes.
Immune cells that circulate in the blood stream and engulf foreign invaders. They can migrate into tissues, where they differentiate into macrophages.
Segmentally repeated subunits of the developing CNS.
An in vitro assay that identifies regions of DNA that are protected from digestion by DNaseI, thereby indicating the presence of bound transcription factors.
- IMAGINAL DISC
Sacs of cells in larval stages of holometabolous insects that divide and differentiate to form most adult tissues.
A balancing organ that is located on the third thoracic segment in Diptera and is an evolutionary modification of a wing.
- Q NEUROBLAST
A C. elegans neural lineage that divides to make QL and QR neuroblasts, which in turn generate identical neural cells on left and right sides of the body.
- CELL AUTONOMOUS
If the activity of a gene has effects only in the cells that express it, its function is said to be cell autonomous; if it causes effects in cells other than (or in addition to) those expressing it, its function is cell non-autonomous.
- RNA-INDUCED SILENCING COMPLEX
A large protein complex that packages microRNAs or siRNAs, silencing expression of proteins from target mRNAs by endonucleolytic cleavage or other unknown mechanisms, depending on the complementarity of mRNA sequences to the packaged small RNAs.
- GNATHAL APPENDAGES
Outgrowths, usually from head segments, that are used to aid feeding.
- RACE CLONES
Partial cDNA sequences that are generated from transcripts by the rapid amplification of cDNA ends (RACE) to determine the start and end points of gene transcription.
- LOCKED NUCLEIC ACID OLIGONUCLEOTIDE PROBES
Modified nucleic acids that have increased thermal stability relative to DNA or RNA when complexed with complementary DNA or RNA.
A major bilaterian subdivision that includes chordates and echinoderms.
One of two major subdivision of bilateria, to which arthropods and molluscs belong.
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Pearson, J., Lemons, D. & McGinnis, W. Modulating Hox gene functions during animal body patterning. Nat Rev Genet 6, 893–904 (2005). https://doi.org/10.1038/nrg1726
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