FIGURE 2:
Bioelectric properties specify instructive, non–cell-autonomous patterning cues. (A) Targeted Vmem change, via misexpression of ion channels in the frog embryo, induces the formation of ectopic structures such as complete eyes, even in regions normally not competent to form eyes (such as on the gut). (Used, with permission, from Figure 3G of Pai et al., 2012.) (B) Tracking the ion channel expression using a lineage marker reveals that the effect is not cell-autonomous: in a lens created in the tail of a tadpole by ion channel expression, only about half of the ectopic cells express the heterologous ion channel (revealed by blue lacZ staining); the other half of the induced structure consists of host cells recruited to participate in making the appropriate shape but not themselves targeted by the Vmem-altering reagent. (C) Melanocytes seen in a cross section of a Xenopus tadpole are normally few in number, round, and confined to their normal locations. (D) Depolarization induced by ion channel modulation induces these cells to overproliferate, acquire an elongated shape, and invade many organs (red arrow). Of importance, this effect is also not cell autonomous, as seen in the melanocyte phenotype, which results when cells (marked by ion channel expression construct lineage label in blue) are depolarized at a considerable distance from the melanocytes. (Taken, with permission, from Figure 6A of Chernet and Levin, 2013b.) (E) A normal planarian has a head and tail and regenerates each at the appropriate end of an amputated fragment. When it is cut into thirds and the middle fragment is briefly exposed to octanol, which temporarily blocks long-range bioelectrical signaling between the wound and mature tissues, a two-headed worm results (F). Remarkably, upon further rounds of cutting in plain water (long after the octanol has left the tissues, as confirmed by HPLC), the two-headed form results (H, I; images of two-headed worms provided by Fallon Durant, Tufts University, Medford, MA). This change in the animal's target morphology (the shape to which it regenerates upon damage) appears to be permanent and persists across the animal's normal reproductive mode (fissioning), despite the fact that the genomic sequence has not been altered. Chromatin modifications alone do not explain this, because the posterior wound cells, which could have been epigenetically reprogrammed to a head fate, are discarded at each cut: the information encoding a bipolar two-head animal is present even in the normal gut fragment—it is distributed throughout the body. We propose that this information is a kind of memory, encoded in electrical networks of somatic cells coupled by gap junctions, and is stored at the level of bioelectrical dynamics. (E–I taken, with permission, from Figure 2 of Levin, 2014; photographs of planaria taken by Taisaku Nogi, Children's Health Research Institute, Canada, and Fallon Durant.)