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A two tier mechanism mediates Hox collinearity. Besides the familiar collinear chromatin modification within each Hox cluster (nanocollinearity), there is also a macrocollinearity tier. Individual Hox clusters and individual cells are coordinated and synchronized to generate multiscale (macro and nano) collinearity in the early vertebrate embryo. Macro-collinearity is mediated by three non-cell autonomous Hox-Hox interactions. These mediate temporal collinearity in early NOM (non-organizer mesoderm), time space translation where temporal collinearity is translated to spatial collinearity along the early embryo's main body axis and neural transformation, where Hox expression is copied monospecifically from NOM mesoderm to overlying neurectoderm in the late gastrula. Unlike nanocollinearity, which is Hox cluster restricted, axial macrocollinearity extends into the head and EAD domains, thus covering the whole embryonic anterior-posterior (A-P) axis. EAD: extreme anterior domain, the only A-P axial domain anterior to the head. The whole time space translation mechanism interacts with A-P signaling pathways via "decision points," separating different domains on the axis.
FIGURE 1. The time space translation hypothesis. Timed interactions between the Hox expressing non-organizermesoderm (NO/N) and the Spemann organizer (S/SO) generate positional information during vertebrate gastrulation (Wacker et al., 2004; Jansen et al., 2007). Expression of new Hox genes (different colors) is initiated in non-organizermesoderm (NO) at different times. Non-organizer mesodermal tissue moves toward the Spemann organizer by convergence and then extends anteriorly (arrow). When mesoderm adjacent to the Spemann organizer involutes (lM), the current Hox code is transferred to overlying neurectoderm (N). While the early Hox sequence in the non-organizermesoderm (solid outlined black box) is running, new cells from this region are continuously moved into the range of Spemann organizer (dashed black box) and their Hox code is then stabilized by an organizer signal. Thus, the temporal Hox sequence is converted into a spatial AP pattern by continuous morphogenetic movement and stabilization of timed information by the organizer in both involuted mesoderm (IM) and overlying neurectoderm (N). 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 five drawings represent paraxial profiles, where the organizer is not visible. The last drawing shows the dorsal side. The black dotted line in the last drawing depicts the sphere of influence of the SO. N, neurectoderm, NO/N, non-organizermesoderm; S/SO, Spemann organizer; A, Anterior; P, Posterior; L, Left; R, Right. The white arrows reflect directions of cell movement flow.
FIGURE 2. Evidence for importance of Hox–Hox interactions in collinearity. Above: Whole A-P axis with EAD genes, head genes and Hox genes. Next: Hox paralog group 1 loss of function phenotype. Expression of all genes including and posterior to Hox1 is compromised (McNulty et al., 2005). The dotted line indicates some genes have a low level of residual expression. Next: Hoxc6 loss of function phenotype. All genes including and posterior to posterior to Hoxc6 have their expression deleted or strongly reduced (Zhu et al., 2017b). Next Hoxb9 gain of function phenotype. A partial posterior axis is induced, starting at Hoxb9 following ectopic expression of Hoxb9 in a hox free dorsalized embryo. Ectopic expression of Hoxd1, Hoxb4, and Hoxb7 each generated comparable partial posterior axes, starting with Hoxd1, Hoxb4, and Hoxb7, respectively (Zhu et al., 2017a).
FIGURE 3. Roles of Hox–Hox interactions in temporal and spatial collinearity and TST. (A) Cross section of Amphibian gastrula, showing NOM and SO. (B) Different stages in TST. Above: Posterior induction and autoregulation (PI and A) are involved in generating temporal collinearity (Zhu et al., 2017a). Middle: the idea that later additional involvement of posterior dominnce/posterior prevalence (PD/PP) may lead to genesis of Hox zones and spatial collinearity by diminishing overlaps in expression and function between successive Hox genes. This is one concept for TST (Zhu et al., 2017a). Below: the spatially collinear pattern.
FIGURE 4. The total picture. Taken together, the different findings provide a time–space translation (TST) mechanism for the whole A-P main body axis. The most anterior part of the dorsal axis (EAD) curls around like the handle of a walking stick to face backwards on the ventral side of the embryo. The CG (Cement gland), a structure formed in this region is so far the earliest induced marker. These findings correlate with decision points in time and space where the traditionally A-P Wnt, retinoid and FGF pathways act. These decision points account for at least some of the well known actions of these pathways on A-P patterning.
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