A non-trivial problem: the maintenance of a single organizing region
Usually the size of a morphogenetic field increases during the growth of the embryo. In a typical reaction-diffusion system a graded concentration profile can be maintained only over a range of about a factor two. With increasing field size, a tendency exists to change from a monotone distribution into a symmetric and ultimately into a periodic pattern either by insertion of new or by splitting of existing maxima. In the simulation below, due to growth, the inhibitor at the non-activated side becomes so low that a new activation is triggered (arrow) and a secondary organizer is formed.
This is inappropriate if the graded concentration should be used in the growing embryo as positional information for the determination of the primary body axes. Multiple maxima would lead to several organizing regions instead and thus possibly to the formation of partially fused embryos.
Some basic biological observations provide important hints of how this wavelength problem has been solved by nature. Hydra maintains its polar structure over substantial growth. Nevertheless, a fragment 1/10 of the normal body size is still able to regenerate. The head regenerates always on the side pointing towards the original head position. Thus, each fragment obviously has an intrinsic polarity. It is the relative position of a cell within a fragment that is decisive whether it will participate in the formation of a head, a foot, or whether it will remain a part of the body column (Gierer, 1977a).
We attribute this polarity to a gradient in the ability of the tissue to perform the pattern-forming autocatalytic reaction, a property we have called source density (blue in the simulation below). This property corresponds to the observable feature of competence. A cell may not be activated for two reasons. Either the feedback loop is down-regulated due to the inhibitor that spreads from a nearby organizing region. Or, the feedback loop cannot be activated since a necessary prerequisite like a co-factor produced by another gene is absent. In the latter case, activation would be impossible even at a low inhibitor level. Therefore, an organizing region is assumed to have a dual and seemingly conflicting effect on the surrounding tissue. On the one hand it inhibits an activation. On the other hand, it maintains the ability to perform the self-enhancing reaction. Therefore, in the course of time, distant regions become unable to generate secondary maxima due to the loss of competence while the pattern-forming reaction remains active close to the organizing region. In this way, a single and still regulating maximum can be maintained even in fields that grow substantially. The graded competence stabilizes the polar pattern by making the induction of additional organizing regions less likely.
During regeneration, the side of the fragment that points towards the original organizer bears the highest competence (blue) and has, therefore an advantage in the competition to regenerate the organizing region (green; see also Hydra ). Depending of how rapidly the competence declines with increasing distance from the original organizer, a fragment may or may not be able to regenerate. In the simulation below, only in the right fragment the competence is high enough such that a new organizer is triggered. In the fragment the competence increases in the course of time to a level typical for a near-organizer position.
Both effects, inhibition and fading of competence, must have different time constants. The inhibition must be a rapid process. After (partial) removal of an organizing region, the inhibition has to decay rapidly in order that regeneration can occur. In contrast, the competence of a tissue should have a much longer time constant. It should remain almost unchanged at the time scale required for pattern regulation.
The spatial restriction of competence is a general phenomenon. In Xenopus, only cells close to the original organizer can regenerate a new one. Likewise, in the chicken, only cells that were originally close to the presumptive notochord regenerate notochordal markers after notochord removal [1,2] and this ability is lost at somewhat later stages. Even in hydra where all parts of the body column can regenerate a new head, tissue fragments derived from positions originally more distant to the head need substantially longer time for head regeneration. Competence may change with time and becomes spatially more restricted. For instance, only at an early stage can an anterior fragment of a chicken blastodisk form a secondary embryo upon fragmentation .
The decline of competence may differ in different species. For instance, unspecific induction of secondary organizing regions at the ‘ventral’ side requires that this region is still competent to form the organizer. The different susceptibilities against unspecific induction of secondary axes in Xenopus and Triturus may have its base in a different fading rate of the competence.
The molecular nature of the graded competence is unknown. As described on the next page, in hydra it can be modified by defined chemicals.
Meinhardt, H. (1993). A model for pattern-formation of hypostome, tentacles, and foot in hydra: how to form structures close to each other, how to form them at a distance. Dev. Biol. 157, 321-333