Figure 5.

The stage-2 “left-right communication” model for the GJC-mediated effects of V_mem change on incidence of tumorigenesis. The “left-right communication” model assumes that the left and right sides of the embryo alternately signal each other to turn the rate of cell division down (A) using an oscillation between polarization and depolarization as the long-range bioelectric signal (B). For example, KRAS^G12D and H7 expressions on opposite sides of the embryo (as shown in Figure 2 treatment C, and sections through a trunk tumor in Panel D) result in an increase in signaling from the H7-injected side and a consequent suppression in KRAS^G12D-induced tumors on the opposite side (C,D). The stage-2 model can be visualized as a control network that regulates cellular response to KRAS^G12D and both the production of ipsilateral signal (IS) and response to contralateral signal (CS). Here unlabeled flat-end arrows indicate a 100% suppressing effect (E). In this model, gap junctions are a central component, contributing to the long-range dynamics by allowing cells to sense neighbors' V_mem. Cellular mechanisms corresponding to these arrows are not yet fully characterized; however, the butyrate—histone deacetylase pathway previously characterized in these embryos (Chernet and Levin, 2013a,b, 2014); is a plausible candidate for transducing the global bioelectrical signal into a local cellular response to KRAS^G12D transformation.