Durston A et al. (2012), Time space translation: a hox mechanism for ver...

XB-ART-47174

Curr Genomics 2012 Jun 01;134:300-7. doi: 10.2174/138920212800793375.

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Time space translation: a hox mechanism for vertebrate a-p patterning.

Durston A , Wacker S , Bardine N , Jansen H .

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The vertebrate A-P axis is a time axis. The head is made first and more and more posterior levels are made at later and later stages. This is different to the situation in most other animals, for example, in Drosophila. Central to this timing is Hox temporal collinearity (see below). This occurs rarely in the animal kingdom but is characteristic of vertebrates and is used to generate the primary axial Hox pattern using time space translation and to integrate successive derived patterns (see below). This is thus a different situation than in Drosophila, where the primary pattern guiding Hox spatial collinearity is generated externally, by the gap and segmentation genes.

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Species referenced: Xenopus
Genes referenced: clock dlc gbx2.1 gbx2.2 hoxa7 hoxb4 hoxb9 hoxc10 hoxc6 hoxc9-like hoxd1

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	Fig. (1). Hox gene phenotypes. The function of Hox genes is defined by gain and loss of function phenotypes. The figure shows this in Drosophila and vertebrates. A. A wild type Drosophila fly This has two wings on the anterior thorax and two halteres (red arrow) on the posterior thorax. B. A four winged fly, caused by a loss of function mutation in ultrabithorax, a gene for posterior thorax [1]. The halteres are transformed to wings. C. Antennapedia mutation: mid thoracic legs replace antennae on the head, due to a misregulated gain of function mutation for the gene Antennapedia (a gene for mid thorax), leading to its expression in the head segments [2]. D. In vertebrates, mouse genetics has been bedevilled by the fact that there are 4 Hox clusters, with parallel functions. This once led to the erroneous idea that vertebrate Hox loss of function mutations have mild phenotypes. In fact, if you knock out all of the paralogues of a particular vertebrate Hox paralogue group (pg), or ectopically express a Hox gene this can give a dramatic phenotype. Left: diagram of wild type Xenopus hindbrain. This has 8 segments (rhombomeres) 2-8 each express a different combination of Hox genes and so have different identities, indicated by the different colours. 1 (white) expresses no Hox genes. Its identity is determined by the gene Gbx2. Middle: hindbrain in Xenopus where Hox pg1 has been knocked down using morpholinos. The hindbrain is drastically anteriorised to the identity of r1. It is also shorter (redrawn from [3]). Right: Skeletons of two mice. Above: wild type. Below, a mouse ectopically expressing HoxC10. The HoxC10 mouse is drastically different. For example, it lacks ribs [4]. The thoracic vertebrae are posteriorised to abdominal identity. This is because Hox pg10 controls the transition from thorax to abdomen, in the vertebral column.
	Fig. (2). Hox Spatial and Functional Collinearity. The four human and one Drosophila Hox complexes are homologues. The colour coding in Panels A and B shows the correspondence between the genomic order of Hox genes in the Hox complexes (A) and their spatial sequence of expression and action zones along the main body axis in Drosophila and human (B) [57].
	Fig. (3). The vertebrate A-P pattern is initiated during gastrulation. Drawings from an Amphibian embryo. From [9]. Top left, late blastula stage, just before gastrulation. Top right and the rest: successive stages through gastrulation, in the order indicated by the arrows. VM: ventral mesoderm, O: organiser mesoderm. VV: ventral endoderm DV: dorsal endoderm. Bc: blastocoels, arch: archenteron. O1, O2, O3, O4 successive A-P levels generated in the mesoderm during gastrulation, from anterior to posterior N1, N2, N3, N4: successive A-P levels in the developing central nervous system, generated in parallel with the mesodermal pattern by vertical signalling.
	Fig. (4). Temporal Collinearity And Time space translation. a. Temporal Collinearity In the Xenopus Gastrula.The figure shows Hox expression patterns at sequential stages during gastrulation in Xenopus. The embryos are seen from underneath, where a ring (the blastopore) shows the position where mesoderm tissue invaginates during gastrulation. This ring gets smaller as gastrulation proceeds and the upper tissues in the embryo spread out and cover the lower part of the embryo (epiboly). The expression of several different Hox genes, seen as blue colour by in situ hybridisation, is in each case initially in the gastrula mesoderm in the zone above (outside) the ring. Hox expression is thus seen as a blue ring, and since it is initially only in part of the mesoderm (non organiser nesoderm), the ring is initially broken. This ring of Hox expression gets smaller as the blastopore ring gets smaller and mesoderm involutes into the embryo. The figure shows expression of a sequence of Hox genes with different paralogue numbers, between 1 and 9. It will be seen that the Hox gene with the lowest paralogue number starts expression first and later numbers start sequentially later. It will also be seen that the Hox genes in this time sequence include members of all of the 4 primary vertebrate paralogue groups (a,b,c,d). b. Time-space translation.Timed interactions between the Hox expressing non-organiser mesoderm and the Spemann organiser generate positional information during Xenopus gastrulation. The drawings [from 11] show simplified 2-dimensional representations of Xenopus gastrulae. The first 5 drawings show parasagittal (ventral to dorsal) two dimensional representations of gastrula profiles, starting at the beginning of gastrulation and then at sequential stages till the end. The last (6th.) drawing shows the end of gastrulation, from the dorsal side (profile at the level of the dorsal axial mesoderm). Hox expressing tissue (NOM (NO and I) and, late in gastrulation neurectoderm (N)) is represented by different colours, each of which represents a different hox code. Initially, the coloured bar represents the broken ring of NOM in the wall of the embryo. The later internal coloured blocks at the dorsal side of the embryo represent the involuted NOM mesoderm. The coloured blocks next to them in the wall of the embryo represent the overlying neurectoderm, which also comes to express hox genes. Hox expression codes are copied from the gastrula mesoderm to the neurectoderm. The SO is shown only in the last drawing, as the heavy median black line. By this stage, it has become the notochord and a head mesodermal portion. The first 5 drawings represent paraxial profiles, where the organiser is not available. The black dotted line in the last drawing depicts the sphere of influence of the SO. N: neurectoderm, NO: non-organiser mesoderm; S,: Spemann organiser; A: Anterior; P: Posterior; L: Left; R: Right. N nonorganiser; S Spemann organiser. The white arrows reflect directions of cell movement flow. To dorsal, anterior and internal(drawings 1 and 6). -There is a collinear time sequence of hox expression in non involuted non-organiser mesoderm (NOM) in the gastrula (depicted by the spectral sequence of colours). -During gastrulation involution movements continuously bring populations of cells from the NOM into the inside of the embryo, where their current Hox code is transiently stabilised. See stack of blocks of different colours, reflecting a history of the collinear hox mesodermal time sequence, in the internal involuted mesoderm. -Stable (ectodermal) Hox expression is induced by a combination of signals from the SO and the Hox expressing NOM. See corresponding blocks of sequential spectral colours in the gastrula's mesoderm and outer layer, reflecting a vertical transfer of the Hox codes from involuted mesoderm to overlying neurectoderm. A “Hox stripe” as part of the anterior–posterior Hox pattern is thus formed at the dorsal side.
	Fig. (5). Some facts and ideas about Hox colinearity. A. Upstream mechanism needed to generate spatial collinearity. In the case that there is no explicit colinearity mechanism, an individual input is needed to turn on each Hox gene to ensure it is expressed at exactly the right axial position. The inputs concerned are going to need an axial pattern themselves. This kind of mechanism is used in Drosophila, where the gap genes and segmentation genes provide the spatial inputs. Gap genes specify the primary axial positions where the Hox genes are expressed and segmentation genes, the Hox genes themselves, polycomb group genes and cofactors like teashirt refine this information, restricting Hox expression by specific segment boundaries. In this situation, the Hox genes thus do not provide the primary axial patterning information. They are secondary. It is likely that this kind of mechanism is general in invertebrates, which usually have no temporal colinearity or colinearity mechanism and have had to evolve an ad hoc mechanism to generate spatial collinearity. Something like this may also occur in the vertebrate hindbrain, where the gastrula’s colinearity mechanism is presumably the primary patterning mechanism and hindbrain genes confirm or alter the patterning information. B. Progressive chromatin opening: the basic idea. This is an idea proposed by Duboule and colleagues to account for vertebrate temporal collinearity. The Hox complex chromatin opens from 3’ to 5’. This opening progressively permits Hox gene transcription, from 3’ to 5’. C. Hox interactions.What regulates vertebrate temporal collinearity? Not just chromatin opening, as proposed by Duboule. The different vertebrate Hox clusters are expressed with synchronous temporal collinearity in the gastrula. The X axis shows time, increasing downwards. The Y axis shows 3’ to 5’ position in a Hox cluster. The figure shows that genes in different clusters are included in the same, temporally collinear sequence. D. What may be involved here are cross interactions between different Hox genes. The figure shows some of the interactions between Hox genes that occur in the vertebrate gastrula. E. A biological clock (the somitogenesis clock) may ensure the timing of Hox temporal collinearity [61]. Periodic pulses of X Delta2 may induce expression of particular Hox genes in NOM mesoderm during gastrulation and later.

References [+] :

Akam, The molecular basis for metameric pattern in the Drosophila embryo. 1987, Pubmed