A serial threshold theory of regeneration

Abstract

A theory of pattern formation in epimorphic regeneration is proposed whose new features are the following: (i) that adult organs consist of a mosaic of discrete territories; (ii) that all of the cells making up a particular territory bear a specific coding, in terms of the states of activity of a set of biochemical switches, (iii) that territories along the axis of an organ are coded in a serial manner which is first established during embryonic pattern formation; and (iv) that the basic processes of regeneration depend on local comparisons of codings in old and new territories. Normally the territories retain their codings and their histological substructure remains differentiated and constant. When, however, a regenerative response is provoked by the presence of a number of permissive factors, the cells in the vicinity of the wound dedifferentiate and can then change their codings by means of interactions with neighbouring tissues. The theory depends on the belief that the two basic processes of regeneration are a “bifurcation” mechanism which establishes the polarity of the blastema, and a “decrementation” mechanism which lays down the new territories in the regenerate. Both mechanisms are present in animals showing bidirectional epimorphic regeneration, and only decrementation is present in animals showing monodirectional epimorphic regeneration. Animals with a morphallactic type of regeneration are assumed to possess a persistent signalling system similar to those believed to exist in embryos. It is proposed that the bifurcation mechanism operates by means of a comparison of codings between the cells near the cut edge and migratory cells derived from the adjacent territories, and results forthwith in the creation of a new extremum with the appropriate terminal coding. Decrementation is so called because the observed sequence in which new parts are created in terminal regeneration is always ‘downwards’. It is assumed that an embryonic field is regionalized by threshold responses of a type discussed previously (Lewis, Slack & Wolpert, 1977) so that all switches are on at the originally dominant end, and that each successive territory has one more switch off. The decrementation process is proposed to operate by means of the local diffusion of the switch products within the blastema, which results in the sequential creation of new territories each having one more switch off than its anterior (or proximal) neighbour. It is shown that intercalary regeneration could work by the same mechanism as terminal regeneration. It is suggested that appendages in insects and vertebrates consist of three dimensional assemblages of territories and that supernumerary regenerates arise from a combination of intercalary regeneration in the transverse axes and distal decrementation in the proximodistal axis. Some biochemical networks are presented which have the dynamical properties required to be able to realize the two basic processes, and some reasons are given for believing that the switch products are glycoproteins.