Bioelectric signals influence facial symmetry

A rare genetic disorder may also shed light on fetal alcohol syndrome and other fetal conditions affecting facial symmetry.

Tufts University biologists have discovered a bioelectric mechanism by which a rare genetic disorder — Andersen-Tawil syndrome (ATS) — causes facial abnormalities. This finding that could lead to preventive measures and treatments for a host of disorders, from birth defects to cancer.

The paper appears in the Journal of Physiology.

Dany Spencer Adams PhD, is research associate professor in the Department of Biology at Tufts' School of Arts and Sciences. Along with colleagues at Tufts, the Massachusetts Institute of Technology and RMIT University. Using a frog embryo as the model animal, for the first time researchers have demonstrated that faulty bioelectric signaling is responsible for the craniofacial defects of ATS — a broad forehead and nose, wide-set eyes, low-set ears and a small jaw and chin.

Patients with ATS have a gene mutation for the potassium ion channel Kir2.1. This is a crucial piece of cell machinery that regulates the flow of positively charged potassium ions through the cell wall. Kir2.1 malfunction affects bilateral symmetry as well as facial features in an embryo.

Cardiac arhythmias and muscle disorders are also associated with ATS having previously been linked to electrophysiology, but craniofacial deformities had never been linked.

The new findings, says Adams: "are not just the first-ever model of why one rare mutation causes craniofacial anomalies. They may apply to the much more common fetal alcohol syndrome."

While perhaps 100 people in the world have ATS, it is estimated more than 7 million suffer from fetal alcohol syndrome. Other research has made note of alcohol binding to the Kir2.1 ion channel. This supports that an abnormal ion channel exchange may cause the distinctive facial features of fetal alcohol syndrome and ATS.

In their study, Tufts scientists used light to control ion channel activity – the first use of optogenetics to manipulate bioelectric signaling to imitate a disease state in an embryo. Using light allowed for precise manipulation of cells genetically modified to express light-sensitive ion channels.

The researchers reveled in how altering natural bioelectric patterns within the outer cell layer of the frog embryo in early development caused such abnormalities in the skull and face. Yet, did not generate changes to appear in later development.

According to Michael Levin, Ph.D., director of the Tufts Center for Regenerative and Developmental Biology and a co-author of the latest study, the work supports earlier research at Tufts regarding bioelectric signaling in cell types other than nerves. Levin feels such signals play a major role in how cells create and repair complex anatomical structures. Levin, who is also the Vannevar Bush Professor in the Department of Biology at Tufts, feels it may be possible to alter bioelectric signals and correct genetic mutations or other developmental defects, "that's the big picture here," adds Levin.

The study suggests an ability may exist to control the Kir2.1 ion channel to dramatically alter developing embryos. Preventing formation of facial abnormalities, such as those associated with ATS and other conditions caused by malfunctioning ion channels, may be possible without altering gene sequence.

"We already have drugs that are approved for human use that alter ion flux. And because we have these targeted drugs, we already have ways to go in and prevent some problems. These bioelectric properties are just as important as biochemical signals and in some ways are much easier targets for therapy than genes."

Dany Spencer Adams PhD

The Adams and Levin labs are two in a handful across the world studying bioelectricity in cells outside of the nervous system.

Abstract
Variants in potassium channel KCNJ2 cause Andersen-Tawil Syndrome (ATS); the induced craniofacial anomalies (CFAs) are entirely unexplained. We show that KCNJ2 is expressed in Xenopus and mouse during the earliest stages of craniofacial development. Misexpression in Xenopus of KCNJ2 carrying ATS-associated mutations causes CFAs in the same structures affected in humans, changes the normal pattern of membrane voltage potential regionalization in the developing face, and disrupts expression of important craniofacial patterning genes, revealing the endogenous control of craniofacial patterning by bioelectric cell states. By altering cells’ resting potentials using other ion translocators, we show that a change in ectodermal voltage, not tied to a specific protein or ion, is sufficient to cause CFAs. By adapting optogenetics for use in non-neural cells in embryos, we show that developmentally-patterned K+ flux is required for correct regionalization of the resting potentials and for establishment of endogenous early gene expression domains in the anterior ectoderm, and that variants in KCNJ2 disrupt this regionalization, leading to the CFAs seen in Andersen-Tawil patients.

"Bioelectric signaling via potassium channels: a mechanism for craniofacial dysmorphogenesis in KCNJ2-associated Andersen-Tawil Syndrome." Dany Spencer Adams, Sebastien G.M. Uzel, Jin Akagi, Donald Wlodkowic, Viktoria Andreeva, Pamela Crotty Yelick, Adrian Devitt-Lee, Jean-Francois Pare, and Michael Levin. Accepted manuscript online: 11 FEB 2016 DOI: 10.1113/JP271930.

Other authors are Sebastien G.M. Uzel, Department of Mechanical Engineering, Massachusetts Institute of Technology; Jin Akagi and Donald Wlodkowic, School of Applied Sciences, RMIT University, Australia; Viktoria Andreeva, formerly of Tufts University School of Dental Medicine; Pamela Crotty Yelick, Tufts University School of Dental Medicine and Sackler School of Graduate Biomedical Sciences at Tufts; and Adrian Devitt-Lee and Jean-Francois Pare, of the Department of Biology and Tufts Center for Regenerative and Developmental Biology, Tufts University.

This work was supported by the National Science Foundation (DBI-1152279); Defense Advanced Research Projects Agency subaward W911NF-11-2-0054; National Science Foundation Science and Technology Center for Emergent Behaviors of Integrated Cellular Systems (CBET-0939511); the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (HD081326, HD081326A, AR061988); Australian Research Council Grant No. DE130101046; Vice-Chancellor's Senior Research Fellowship, RMIT University, Australia; and The Australia Endeavour Awards, Department of Education, Employment and Workplace Relations, Australia.

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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Tadpole on the LEFT has regular, symmetrical craniofacial features of normal embryo development.
Faulty bioelectric signaling is responsible for the skull and facial abnormalities (RIGHT) characteristic of
the genetic disorder Andersen-Tawil Syndrome (ATS). Research shows it may be possible to alter these signals
and correct similar facial effects also found in fetal alcohol syndrome, or perhaps other developmental
defects and genetic mutations associated with faulty potassium ion channel Kir2.1.
Image Credit: Adams Laboratory at Tufts University