Long-Distance Signals Are Required for Morphogenesis of the Regenerating Xenopus Tadpole Tail, as Shown by Femtosecond-Laser Ablation

Abstract

BackgroundWith the goal of learning to induce regeneration in human beings as a treatment for tissue loss, research is being conducted into the molecular and physiological details of the regeneration process. The tail of Xenopus laevis tadpoles has recently emerged as an important model for these studies; we explored the role of the spinal cord during tadpole tail regeneration.Methods and ResultsUsing ultrafast lasers to ablate cells, and Geometric Morphometrics to quantitatively analyze regenerate morphology, we explored the influence of different cell populations. For at least twenty-four hours after amputation (hpa), laser-induced damage to the dorsal midline affected the morphology of the regenerated tail; damage induced 48 hpa or later did not. Targeting different positions along the anterior-posterior (AP) axis caused different shape changes in the regenerate. Interestingly, damaging two positions affected regenerate morphology in a qualitatively different way than did damaging either position alone. Quantitative comparison of regenerate shapes provided strong evidence against a gradient and for the existence of position-specific morphogenetic information along the entire AP axis.ConclusionsWe infer that there is a conduit of morphology-influencing information that requires a continuous dorsal midline, particularly an undamaged spinal cord. Contrary to expectation, this information is not in a gradient and it is not localized to the regeneration bud. We present a model of morphogenetic information flow from tissue undamaged by amputation and conclude that studies of information coming from far outside the amputation plane and regeneration bud will be critical for understanding regeneration and for translating fundamental understanding into biomedical approaches.

An automated training paradigm reveals long-term memory in planaria and its persistence through head regeneration

“…However, such results are now made more plausible by modern discoveries such as epigenetic modification, which occurs in many cell types, not just the CNS (Arshavsky, 2006;Day and Sweatt, 2010;Ginsburg and Jablonka, 2009;Levenson and Sweatt, 2005;Zovkic et al, 2013) and RNAi (Smalheiser et al, 2001). It is likely that brain remodeling (plasticity during learning) and regeneration are both regulated via epigenetic pathways that determine patterns of self-organization of neural (Arendt, 2005;Davies, 2012;Kennedy and Dehay, 2012;Saetzler et al, 2011) and non-neural but electrically communicating cells (Levin, 2012;Mondia et al, 2011;Oviedo et al, 2010;Tseng and Levin, 2013).…”

“…It has long been known that regeneration both shapes and is in turn guided by activity of the CNS (Geraudie and Singer, 1978;Mondia et al, 2011;Singer, 1952). Thus, it is possible that experiences occurring in the brain alter properties of the somatic neoblasts and are in turn recapitulated back during the construction of the new brain by these adult stem cells.…”

Re-membering the body: applications of computational neuroscience to the top-down control of regeneration of limbs and other complex organs

“…Examples include the control of proliferation and differentiation by the signaling dynamics of neural networks 98 , the induction of spinal cord regenerative rewiring by electrical activity 99 , the mispatterning of deer antler regeneration by neural inputs 100 , and the known dependence of regenerating salamander limbs on 101 , and addiction to 102 , nerves. Importantly, the role of neural inputs in regeneration pattern is not merely permissive, but rather carries instructive information, as revealed by the determination of head vs. tail morphogenesis by the directionality of a transplanted nerve cord 103 , the induction of distinct shapes in a regenerated tadpole tail from different locations of damage to the spinal cord very far away from the wound site 104 , or the control of seashell patterning by specific neural net output 105 .…”

Morphogenetic fields in embryogenesis, regeneration, and cancer: Non-local control of complex patterning

“…In planaria, the integrity of the ventral nerve cord is actually required to specify appropriate fate for a regeneration blastema: if the VNC is cut in a gap junction-inhibited worm, an ectopic head can result (Oviedo et al, 2010). The pattern of regenerating tails is markedly different from the normal pattern if spinal cord contiguity is interrupted by a laser pulse at points far away from the tail amputation in Xenopus tadpoles (Mondia et al, 2011) or surgical perturbations of the brain/spinal cord (Hauser, 1969; Jurand et al, 1954). Moreover, the shape alterations are different when the spinal cord is targeted at different positions along the anterior-posterior axis, and two individual spots of interruption produce a phenotype distinct from that resulting from either spot alone.…”