The nervous system and regeneration of the forelimb of adult triturus. VI. A further study of the importance of nerve number, including quantitative measurements of limb innervation

Abstract

As has been shown repeatedly in the past, denervation of the amputation stump of the urodele limb successfully prevents subsequent regeneration. This fact has l e d l o a number of studies of the relation of the nerve to the regeneration process. Notable among these has been the analysis of the action of the individual nerve components in the influence of the nerve on regeneration (see Singer, '42-'46 for review). In a series of studies of which the present paper is the sixth, the problem of the activity of the individual nerve components has been reanalyzed (Singer, loc. cit.). The results which have emerged from these investigations permit a revaluation of our views on the relation of nervous activity to the regeneration process as observed in amphibians. Of the 3 nerve components (sensory, motor and sympathetic) which supply the forelimb, only the sensory is capable of stimulating regeneration in the absence of the other 2. The effectiveness of the sensory component does not appear to be due to a special quality of its fibers not enjoyed by other neural elements, but rather to a quantitative superiority. The anatomy of the peripheral nervous system favors the sensory component, 223

Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration

“…In Urodeles, surgical denervation before amputation results in the inhibition of blastema formation, and ultimately results in regeneration failure. Evidence from fish and amphibians suggests that nerve dependence may be a function of a threshold level of nerve factors with a direct correlation between nerve fibers and degree of regeneration (3,11,12) and supports the idea that nerve dependence may be an evolutionarily conserved requirement for the regeneration of vertebrate limb tissues.Mammalian limbs consist of multiple tissues that are derived from various embryonic origins and germ layers, including embryonic ectoderm, embryonic mesoderm, and embryonic neuralcrest. Recent lineage-tracing studies have demonstrated that tissue-resident stem and progenitor cells that are fate-restricted in their developmental potential are responsible for appendage regeneration of fish, salamanders, and mice (13-16).…”

“…In Urodeles, surgical denervation before amputation results in the inhibition of blastema formation, and ultimately results in regeneration failure. Evidence from fish and amphibians suggests that nerve dependence may be a function of a threshold level of nerve factors with a direct correlation between nerve fibers and degree of regeneration (3,11,12) and supports the idea that nerve dependence may be an evolutionarily conserved requirement for the regeneration of vertebrate limb tissues.…”

“…An abundance of data across several vertebrate taxon groups (3,11,12) suggests that nerves may have a conserved evolutionary role that is essential to, or permissive for, limb regeneration. Despite the absence of innervation to the hind limb throughout the time of regeneration, the mouse model replaces the amputated digit tip with surprising fidelity in most tissue types.…”

Mechanisms of urodele limb regeneration

“…Marcus Singer carried out a comprehensive series of studies on the role of the brachial nerves (spinal nerves 3, 4, and 5) in regeneration of the adult newt forelimb (Singer, 1942, 1943, 1945, 1946a, b, 1947a, b; Singer & Egloff, 1949) which revealed that a threshold number of axons (later expressed as amount of axoplasm per unit area of newt limb tissue) is required for regeneration, and that the threshold is different at different PD levels of the limb. The results of these studies were synthesized into the neurotrophic hypothesis (Singer, 1952, 1964, 1965), which states that the nerves provide a threshold level of trophic factors essential for the survival and proliferation of blastema cells.…”

A stepwise model system for limb regeneration

“…Denervated late stage blastemas similarly do not regress, but their growth is inhibited and they eventually form a miniature regenerate. The nerve requirement is quantitative, and below a threshold number of nerves, neither bumps nor blastemas are formed (Bodemer, 1960;Singer, 1947). In both, nerves grow distally and innervate the apical epidermis, and in both bumps and regenerates, nerves appear to be involved directly or indirectly in regulating the growth permissive function of the epidermis.…”