Molecular bioelectricity in developmental biology: new tools and recent discoveries: control of cell behavior and pattern formation by transmembrane potential gradients - PubMed (original) (raw)

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Molecular bioelectricity in developmental biology: new tools and recent discoveries: control of cell behavior and pattern formation by transmembrane potential gradients

Michael Levin. Bioessays. 2012 Mar.

Abstract

Significant progress in the molecular investigation of endogenous bioelectric signals during pattern formation in growing tissues has been enabled by recently developed techniques. Ion flows and voltage gradients produced by ion channels and pumps are key regulators of cell proliferation, migration, and differentiation. Now, instructive roles for bioelectrical gradients in embryogenesis, regeneration, and neoplasm are being revealed through the use of fluorescent voltage reporters and functional experiments using well-characterized channel mutants. Transmembrane voltage gradients (V(mem) ) determine anatomical polarity and function as master regulators during appendage regeneration and embryonic left-right patterning. A state-of-the-art recent study reveals that they can also serve as prepatterns for gene expression domains during craniofacial patterning. Continued development of novel tools and better ways to think about physical controls of cell-cell interactions will lead to mastery of the morphogenetic information stored in physiological networks. This will enable fundamental advances in basic understanding of growth and form, as well as transformative biomedical applications in regenerative medicine.

Copyright © 2012 WILEY Periodicals, Inc.

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Figures

Figure 1

Figure 1

Control of cell state by transmembrane potential. A sample of physiological measurements of various cell types (modified from [108]) reveals that quiescent, terminally differentiated cells tend to be strongly polarized, while more plastic cell types (stem cells, embryonic cells, and cancer cells) tend to be relatively depolarized. Interestingly, the liver's Vmem (abnormally low for an adult differentiated tissue) groups it with the morphogenetically labile cells, consistent with its remarkable regenerative potential. The relationship between Vmem and plasticity is a functional one; for example, mature neurons can be induced to re-enter the cell cycle by forced depolarization [109].

Figure 2

Figure 2

Voltage gradients in vivo. A: Fluorescent voltage reporter dyes allow characterization of physiological gradients in vivo, such as this image of a 16-cell frog embryo that simultaneously reveals cells' potential levels (blue = hyperpolarized, red = depolarized) in vivo, as well as domains of distinct Vmem around a

single

blastomere's surface (compare the side indicated by the yellow arrowhead with the one indicated by the red arrowhead). B: Gradients of transmembrane potential demarcate important tissue domains, such as the depolarized region shortly after tail amputation in Xenopus laevis tadpoles (blue arrowhead), which will give rise to the regeneration bud, and can reveal non-regenerative conditions when the appropriate physiological state had not been achieved, or was experimentally blocked (yellow arrowhead). C: Isopotential cell fields can also demarcate subtle prepatterns existing in tissues, such as the hyperpolarized domains (red arrowheads) that presage the expression of regulatory genes such as Frizzled during frog embryo craniofacial development [13]. It is necessary to gain a quantitative understanding of the bioelectric code – to map out the linkage between physiological state with cell behavior outcomes, as a prelude to a full understanding of how 3-dimensional patterning information is stored in physiological properties of tissue. D: One hypothesis is that cell types (e.g. proliferative, or neoplastic, or undifferentiated) cluster in a multi-dimensional state space in which each axis defines the value of a physiological parameter. Additional axes (not shown) could include levels of other ions (chloride, potassium), nuclear membrane potential, cell surface charge (zeta potentials), etc. Once appropriate data are gathered, cells could be moved from their current state to a desired state by pharmacological and molecular-genetic changes shifting them along each axis, toward a different ensemble within the state space as needed for a given biomedical application.

Figure 3

Figure 3

A framework for modeling bioelectrical signaling. A comprehensive model synthesizing bioelectrical and genetic pathway elements must integrate physiological descriptions of the ion channels and pumps expressed in cells into a quantitative picture of the voltage gradients, their effects on movement of small signaling molecules through gap junctions and membrane transporters, and ultimately effects on second messenger pathways and transcriptional responses. Here is shown a representative system (motivated by current models of early left-right patterning of frog embryos; the schematic was modified after Fig. 7B of [110] drawn by Junji Morokuma). Differential expression and function of well-characterized channels and pumps (e.g. V-ATPase, KCNQ1, and Katp) form circuits that establish distinct Vmem levels in different cells; this process can be mathematically modeled (as has been done for kidney, lens, and inner ear tissues) based on the known physiological properties of the translocators involved. The resulting voltage gradients gate gap junction connectivity states between adjacent cells, as well as exert electromotive force that regulates the movement of small signaling molecules (e.g. 5HT serotonin). This movement can be simulated using particle-tracking or differential equations. The resulting morphogen gradients can activate transcriptional changes, setting up prepatterns of gene expression that mirror the earlier voltage gradients, regionalizing tissues and closing the link between bioelectric events and specification of anatomy.

Figure 4

Figure 4

Physiological profiling. A: Cells exhibiting very different expression profiles for ion transporter genes can indeed be in similar physiological states (B), based on overlapping functions for the transporters. Lack of 1:1 mapping between expression of channels/pumps and physiological state (due to compensation by other family members and post-translational gating) means that important information about cell behavior is not captured by molecular-genetic analysis without physiological profiling. Nevertheless, transcriptional data can suggest hypotheses for functional validation: the GEO database [111] can be mined for ion channel/pump profiles, such as the increased expression of the Clic6 chloride channel during HSC maturation (C), and the changes in the expression of sodium channels during progression towards melanoma in skin cells (D).

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