Long-Term, Stochastic Editing of Regenerative Anatomy via Targeting Endogenous Bioelectric Gradients

Abstract

We show that regenerating planarians' normal anterior-posterior pattern can be permanently rewritten by a brief perturbation of endogenous bioelectrical networks. Temporary modulation of regenerative bioelectric dynamics in amputated trunk fragments of planaria stochastically results in a constant ratio of regenerates with two heads to regenerates with normal morphology. Remarkably, this is shown to be due not to partial penetrance of treatment, but a profound yet hidden alteration to the animals' patterning circuitry. Subsequent amputations of the morphologically normal regenerates in water result in the same ratio of double-headed to normal morphology, revealing a cryptic phenotype that is not apparent unless the animals are cut. These animals do not differ from wild-type worms in histology, expression of key polarity genes, or neoblast distribution. Instead, the altered regenerative bodyplan is stored in seemingly normal planaria via global patterns of cellular resting potential. This gradient is functionally instructive, and represents a multistable, epigenetic anatomical switch: experimental reversals of bioelectric state reset subsequent regenerative morphology back to wild-type. Hence, bioelectric properties can stably override genome-default target morphology, and provide a tractable control point for investigating cryptic phenotypes and the stochasticity of large-scale epigenetic controls.

Post-SSRI Sexual Dysfunction: A Bioelectric Mechanism?

“…Planaria whose bioelectric circuits are briefly modulated by small molecule drugs experience an alteration in bioelectric patterns within their tissues that are apparently permanent and persistently affect their cell-and tissue-level functions long after the original drugs are withdrawn. [38][39][40] This occurs over many months and is (as far as is known) permanent, despite the rapid turnover of all of their somatic cells within a few weeks.…”

Nervous System and Tissue Polarity Dynamically Adapt to New Morphologies in Planaria

“…including manipulation of bioelectric signaling (Durant et al, 2017;Oviedo et al, 2010) or interference 92 with the Wnt signaling pathway (C. P. Petersen & Reddien, 2008). Newly regenerated DHs (7 days after 93 transection of the single-headed animal) of the species Dugesia japonica show developmental differences 94 between their two heads: the head regenerated from the anterior blastema is more fully regenerated 95 than the head positioned on the original tail end of the animal, based on criteria such as eye development, 96 head shape, and blastema coloration ( Figure 1A i-iii).…”

“…Spring water and allowed to regenerate at 20 °C (Durant et al, 2017). Double-head regenerative outcomes 602 were scored 7 days after cutting by the presence of a head, marked by at least one eye spot, on either 603 end of the fragment.…”

Space travel has effects on planarian regeneration that cannot be explained by a null hypothesis

“…“[E]xposure of the pharyngeal pieces of the worms to conditions in the International Space Station started only approximately 78 h after amputation and that thus regenerative processes were already well in progress.” S&S may be unaware that, even 3 days after amputation, regenerative patterning decisions can be over‐ridden (Durant et al., 2017, Fig. 2).…”

“…Not only have there been many reports (both classical [Brøndsted, 1969] and recent [Umesono, Tasaki, & Nishimura, 2013]) about significant native differences in regenerative ability and other outcomes among planaria, we (and the planarian community as a whole) are well aware of the considerable differences in response of, for example, D. japonica and S. mediterranea , to drugs, RNAi, and various environmental stressors. As just another example, octanol causes bipolarity in D. japonica (Durant et al., 2017), but changes of head shape in Girardia dorotocephala (Emmons‐Bell, Durant, & Hammelman, 2015). …”