Hox gene

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Hox genes are a family of regulatory genes . Their gene products are transcription factors that control the activity of other functionally related genes in the course of individual development ( morphogenesis ). So they belong to the homeotic genes .
The characteristic component of a Hox gene is the homeobox . It is a characteristic sequence of homeotic genes. The homeoboxes code in the cells for delimitable specific protein areas or protein domains (homeodomains). These usually consist of 60 amino acids and have a DNA binding domain. The base sequence of the homeobox is very similar in all Hox genes of all animal species. This leads to the conclusion that they already early in the evolutionary history preserved has been; obviously mutations are usually fatal here.

Metaphase chromosome (scheme):
1   one of the two chromatids (blue)
2   on the centromere (red) the two chromatids are attached - this is where the microtubules attach in mitosis .
3   short arm (p-arm)
4   long arm (q-arm)
Schematic representation of a Hox gene cluster on one arm of the chromatid (the centromere is on the left)

tasks

The primary task of the Hox genes is to structure the embryo along the longitudinal axis of the body (anatomically: cranio-caudal axis). They fulfill this task in all animals that have a body axis. Different strains or orders have different numbers of Hox genes during embryonic development, each in a particular section expressed are. This results in a sequence of stripes within the embryonic tissue. The cells in this strip receive positional information about their position in the developing embryo; their further division, their differentiation and possibly their programmed cell death ( apoptosis ) then take place according to this situation. The training and specific shape of the extremities is particularly striking . In insects, the Hox genes determine whether extremity appendages develop in a segment. Later they regulate what kind of extremities are formed (e.g. antennae , mouthparts , legs, wings ). In the vertebrate embryo (also in humans), the Hox genes determine, among other things, the formation and shape of the vertebrae (cervical vertebrae, thoracic vertebrae, lumbar vertebrae) and ribs. The trunk groups of insects (Arthropoda) and vertebrates (Chordata) are segmented organisms. However, Hox genes are involved in the organization in the same way in organisms without segments.

The second body axis of the bilateria , the back-front axis (anatomically: dorsal-ventral axis) is not controlled by Hox genes. Other transcription factors are responsible for their determination : decapentaplegic or bone morphogenetic protein (Dpp / Bmp) and short gastrulation or chordin (Sog / Chrd).

evolution

The Hox genes are just one part of a larger family of genes, each with similar functions. In addition to the Hox genes, there are also families of the ParaHox genes and the so-called NK genes (named after their discoverers, Niremberg and Kim). Together with a few other, smaller gene families, they form what is known as the ANTP megacluster. The respective families may have special relationships with one of the embryonic cotyledons : Hox to the neuroectoderm , ParaHox to the endoderm , NK to the mesoderm . If this theory were confirmed, it would have profound implications for the reconstruction of the common family tree of the animal phyla.

All genes belonging to this subheading show such great agreement in their base sequence, even outside the homeobox, that it is assumed that they were created by gene duplication from a single original gene. Genes from the ANTP megacluster were found in all of the multicellular animals examined. They did not occur in any unicellular organisms ( Protozoa ) investigated to date , especially not in the choanoflagellates , which are generally regarded as the sister group of multicellular animals, i.e. H. are closest related to them among the unicellular organisms. The gene family must have already existed with the common ancestor of all Metazoa (in the Precambrian). Actual Hox genes are common to all animal phyla with the exception of the sponges , the comb jellyfish (and possibly the placozoa ). In the cnidarians (Cnidaria) there are two Hox genes. The most primitive Bilateria, the Acoelomorpha , have four. In all more highly organized animal phyla, the situation becomes more complicated because individual Hox genes have split (doubled) and others have disappeared in different lines. As a result, the remaining Hox genes do not always correspond directly, even if their number may be the same. Arthropods and mollusks , for example, each have nine Hox genes.

The conditions are most complicated in the overstem of the Deuterostomia , to which the vertebrates also belong. The lancet fish Amphioxus , the last surviving representative of the skullless (Acrania), which are considered the closest relatives of the ancestor of the higher vertebrates, has fifteen Hox genes. The four-footed vertebrates ( Tetrapoda ) have 39 Hox genes, which can be divided into four gene clusters . It is now widely believed that the vertebrate genome (including the Hox genes) has completely doubled twice in the course of evolution. The current number comes from the subsequent loss of individual genes at a later point in time. Different lines of development of the bony fish , in which there was further duplication of genes after the splitting off of the Tetrapoda, have even more Hox genes.

The Hox genes of all higher organized tribes can be assigned to four gene families, which are traced back to the four Hox genes of the Urbilaterier. The individual genes within the different strains can in many cases be parallelized on the basis of their base sequences, that is, they presumably originated from the same original gene in the common ancestor of both lines ( homologous ).

regulation

Hox gene distribution in a mouse ( vertebrate ) embryo
Hox gene distribution in Drosophila melanogaster ( invertebrates )

Hox proteins are transcription factors that assign different identities to different parts of the body. This is done by regulating numerous genes behind it (in the jargon of geneticists: “ downstream ”), many of which are controlled by several Hox proteins. In a particular segment , small differences in the location and timing of Hox gene expression play an important role in the fate of developing organs and cell lines. Some Hox genes have taken on roles in addition to cellular pattern formation (position information).

What is particularly striking is that the sequence of the Hox genes on the chromosome corresponds to the sequence of the body sections they control. At least in the case of vertebrates, this corresponds to the sequence of their temporal expression. In addition, the Hox genes are usually arranged in a single (or a few) sections directly adjacent on the DNA strand. This regular arrangement suggests underlying regulatory processes that are preserved in large parts of the animal kingdom. It is called colinearity , a pioneering term associated with the geneticist Denis Duboule .

Hox genes act on other transcription factors, but also on numerous (sometimes hundreds) effector genes, which they can switch on or off like a switch. To do this, like all transcription factors, they attach to a section (so-called cis-regulatory sequence ) adjacent to the protein-coding sequence of the gene . Hox genes are controlled by other transcription factors that were previously expressed in the organization. These controlling elements are extremely difficult to research in detail. Some findings are available from the geneticists' most important model organism, the fruit fly Drosophila . Accordingly, the regulatory sequences are organized in modules, each of which is shielded from one another by "buffers" (separating elements). While the base sequence of the Hox genes is evolutionarily conserved, the cis-regulatory segments have already proven to be very different in eight different species of fruit flies. Within this variable overall ensemble, however, there are obviously shorter domains that are so similar between the different species that switches of one species could be controlled by proteins of another species. Initiator elements within the respective module decide on the expression of the individual Hox gene. There are also other regulatory proteins that can switch off entire modules or keep them in an expressive state by changing the "packaging" of the DNA in chromatin- histone complexes. Overall, the situation is extremely complicated and research into it is still in its infancy. The order of magnitude can be estimated, for example, from the fact that the regulatory sequences make up 98 percent of the total size of a certain Hox gene from Drosophila (Ubx), and the protein-coding section 2 percent.

If a Hox protein is expressed in the wrong part of the body (ectopically) through a natural or artificially generated mutation, this has serious consequences for development. Serious malformations result, in which organs or body attachments arise in the wrong place and the identity of entire segments in the body can change. One speaks here of homeotic transformations or mutations. For example, instead of antennae, legs can grow in the fruit fly ("Antennapedia"), or instead of abdominal segments, the thoracic segments are doubled ("Bithorax"). Such homeotic mutations were discovered by geneticists as early as 1915. They eventually led to the discovery of the Hox genes. Homeotic mutations usually lead to death. In humans z. B. the formation of additional fingers ( polydactyly ) probably due to a homeotic mutation.

Evolutionary developmental biology

The discovery of the Hox genes was probably the most important trigger for the emergence of a new research direction : evolutionary developmental biology , often abbreviated as "Evo-Devo". Since it was now possible for the first time to directly research the genetic basis for fundamental developmental mechanisms, the special importance of individual (ontogenetic) development for evolution has become the basis for a completely new research program. What is important about the importance of developmental mechanical constraints on the direction and speed of evolutionary processes is that for the first time an actual genetic basis for basic body plans, and thus possibilities for their evolutionary change, are recognizable. By different expression of Hox genes, processes such as z. B. understand the development of the body sections (Tagmata) of the insects from similarly segmented precursors or the formation of the body plan of the snakes from lizard-like precursors. Further essential findings concern the relationships based entirely on the pedigree of the animals. Processes that were previously completely puzzling, such as the origin of the animal phyla, are now much easier to understand.

There are still controversial ideas within science about the actual role of the Hox genes themselves in these changes. Some scientists are of the opinion that new body plans can be created in one step via a small mutation. So you imagine the creation of a new blueprint as a very rare, inexpensive homeotic transformation. Most scientists, however, disagree. They have developed models of how small shifts in the ratio of different Hox proteins can result in the same changes very gradually .

literature

  • Douglas J. Futuyma , Scott V Edwards, John R True: Evolution. The original with translation aids (= easy reading. ). 1st edition, Elsevier, Munich 2007, ISBN 978-3-8274-1816-6 .
  • Rüdiger Wehner, Walter Gehring, Alfred Kühn: Zoology . 24th, completely revised edition, Thieme, Stuttgart 2007, ISBN 978-3-13-367424-9 .
  • Edward B. Lewis: A gene complex controlling segmentation in Drosophila. In: Nature . Volume 276, December 1978, pp. 565-570, doi: 10.1038 / 276565a0 .
  • Shigehiro Kuraku, Axel Meyer: The evolution and maintenance of Hox gene clusters in vertebrates and the teleost-specific genome duplication. In: International Journal of Developmental Biology. 53, 2009, pp. 765-773.
  • Gabriel Gellon, William McGinnis: Shaping animal body plans in development and evolution by modulation of Hox expression patterns. In: BioEssays. 20.2, 1998, pp. 116-125.
  • Joseph C. Pearson, Derek Lemons, William McGinnis: Modulating hox gene functions during animal body patterning. In: Nature Reviews Genetics. 6, 2005, pp. 893-904.
  • Denis Duboule : The rise and fall of Hox gene clusters. In: Development. 134, 2007, pp. 2549-2560.
  • Graham E. Budd: Does evolution in body patterning genes drive morphological change - or vice versa? In: BioEssays. 21, 1999, pp. 326-332.
  • Michalis Averof, Michael Akam: Hox genes and the diversification of insect and crustacean body plans. In: Nature. Volume 376, No. 3, August 2002, pp. 420-423, doi: 10.1038 / 376420a0 .
  • Jordi Garcia-Fernàndez: The genesis and evolution of homeobox gene clusters. In: Nature Reviews Genetics . 6, 2005, pp. 881-892.
  • Robert K. Maeda, François Karch: The ABC of the BX-C: the bithorax complex explained. In: Development. 133, 2006, pp. 1413-1422.

Web links

Individual evidence

  1. ↑ Kevin Pang, Mark Q. Martindale: Developmental expression of homeobox genes in the ctenophore Mnemiopsis Leidyi. In: Development Genes and Evolution. 218, 2008, pp. 307-319.
  2. ↑ Stephen J. Gaunt, Paul T. Sharpe, Denis Duboule: Spatially restricted domains of home gene transcripts in mouse embryos: relation to a segmented body plan. In: Development. Volume 104, Supplement, October 1988, pp. 169-179 ( full text as PDF file ).
  3. ↑ JC Izpisua-Belmonte, H. Falkenstein, P. Dolle, A. Renucci, D. Duboule: Murine genes related to the Drosophila AbdB homeotic genes are sequentially expressed during development of the posterior part of the body. In: The EMBO journal. (Embo J) Vol. 10, No. 8, August 1991, pp. 2279-2289, PMID 1676674 .