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Bioelectric signals reflect across cell membranes. Signals are unique to different cell types. New data finds that embryonic voltage is also instructing formation of the brain.

Bioelectricity key in brain development and repair

More than on/off switch, electric signals tell cells where and how to grow. Research conducted by Tufts University shows that bioelectrical signals control and instruct embryonic brain development.

Manipulating these signals may help repair genetic defects and induce healthy brain development in locations it would not ordinarily grow.

The research reveals that bioelectric signaling regulates the activity of two reprogramming factors — proteins that turn adult cells into stem cells. These factors were analyzed for the first time in embryos of the frog Xenopus laevis, as they share evolutionary traits with humans. Results appeared March, 2015, in the Journal of Neuroscience.

"We've found that cells communicate in the embryo, even across long distances, using bioelectrical signals. With this information, cells know where and how big a brain should become."

Michael Levin PhD, Vannevar Bush Chair in Biology, Director  Center for Regenerative and Developmental Biology, School of Arts and Sciences,Tufts — and corresponding author.

Bioelectric signals reflect changes in the voltage across cell membranes — called the cellular resting potential — and patterns of differential voltage across anatomical regions. These signals are unique to different cell types, including mature somatic cells and stem cells. Prior work in Levin's lab revealed unique bioelectric gradients in eye, limb and visceral organs. This new paper reveals that natural embryonic voltage gradients are also instructing formation of the brain.

"This latest research also demonstrated molecular techniques for 'hijacking' bioelectric communication in order to force the body to make new brain tissue. And possibly, help fix genetic defects that cause brain malformation. This means we may be able to induce growth of new brain tissue, which is very exciting."

Michael Levin PhD

One area of interest is the Notch signaling pathway, a protein signaling system known to play a strong role in neural growth and differentiation. Defects in Notch signaling have been linked to T-cell acute lymphoblastic leukemia and multiple sclerosis. Tufts' research team used molecular reconstructions to correct weak bioelectrical states and override defects induced by Notch malfunctions. Laboratory results ended with much more normal brain function despite a genetically defective Notch.

"Using bioelectric signals to control tissue shape doesn't require micromanaging the genetics of the cells, which can have severe adverse effects."

Vaibhav Pai PhD, first author, research associate Levin lab.

Bioelectricity and reprogramming factors work together to regulate tissue fate, adds Levin. "Additional study will help us fully understand which electric signal interacts with which genetic network. With this work we reveal two steps, [1] involving calcium signaling and [2]cell to cell communication via electrical synapses known as gap junctions.

"We are working on applying these techniques to ion channel modifying drugs — electroceuticals — to repair defects and induce brain regeneration."

Michael Levin PhD

Abstract
Biophysical forces play important roles throughout embryogenesis, but the roles of spatial differences in cellular resting potentials during large-scale brain morphogenesis remain unknown. Here, we implicate endogenous bioelectricity as an instructive factor during brain patterning in Xenopus laevis. Early frog embryos exhibit a characteristic hyperpolarization of cells lining the neural tube; disruption of this spatial gradient of the transmembrane potential (Vmem) diminishes or eliminates the expression of early brain markers, and causes anatomical mispatterning of the brain, including absent or malformed regions. This effect is mediated by voltage-gated calcium signaling and gap-junctional communication. In addition to cell-autonomous effects, we show that hyperpolarization of transmembrane potential (Vmem) in ventral cells outside the brain induces upregulation of neural cell proliferation at long range. Misexpression of the constitutively active form of Notch, a suppressor of neural induction, impairs the normal hyperpolarization pattern and neural patterning; forced hyperpolarization by misexpression of specific ion channels rescues brain defects induced by activated Notch signaling. Strikingly, hyperpolarizing posterior or ventral cells induces the production of ectopic neural tissue considerably outside the neural field. The hyperpolarization signal also synergizes with canonical reprogramming factors (POU and HB4), directing undifferentiated cells toward neural fate in vivo. These data identify a new functional role for bioelectric signaling in brain patterning, reveal interactions between Vmem and key biochemical pathways (Notch and Ca2+ signaling) as the molecular mechanism by which spatial differences of Vmem regulate organogenesis of the vertebrate brain, and suggest voltage modulation as a tractable strategy for intervention in certain classes of birth defects.

Additional authors on the paper are Joan M. Lemire, and Jean-Francois Pare, research associates in the Department of Biology and Center for Regenerative and Development Biology at Tufts, and Gufa Lin and Ying Chen, of the Stem Cell Institute at the University of Minnesota.

Research reported in this release was supported by the National Institutes of Health under award numbers AR055993-01 and 1R01HD081326-01, the National Science Foundation under award number CBET-0939511 and the G. Harold and Leila Y. Mathers Charitable Foundation.

Endogenous Gradients of Resting Potential Instructively Pattern Embryonic Neural Tissue via Notch Signaling and Regulation of Proliferation, Vaibhav Pai, Joan M. Lemire, Jean-Francois Pare´, Gufa Lin, Ying Chen, and Michael Levin, Journal of Neuroscience, March 11, 2015, DOI:10.1523/JNEUROSCI.1877-14.2015

Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoy a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university's schools is widely encouraged.

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