Craniofacial development in tractable models such as the frog Xenopus, has been a popular and highly rewarding model for studies of the cell activities that build complex structures. Much information has been gathered about the chemical and genetic processes that underlie craniofacial patterning. In contrast to and complementing that work, our lab has discovered a layer of biophysical signaling: a regulated distribution of different cell membrane resting potentials that instruct cell behavior and large-scale morphogenesis. We have showed that eye development, limb regeneration, and tumorigenesis are all regulated by ion channel-mediated voltage gradients. We have adapted voltage-sensitive fluorescent dyes to observe these gradients and used molecular tools to modify them thereby regulating individual cell behaviors and reprogramming whole organ primordia. These techniques are distinct from classical methods of electric field application, and reveal not only the molecular-genetic sources of the gradients but also the epigenetic and transcriptional downstream steps through which biophysical properties regulate morphology. Recently, we uncovered a remarkable feature of early craniofacial development: the "electric face" - dynamic patterns of hyper- and depolarization in the embryonic frog face that precede, predict, and control the shape and location of facial structures. Perturbing these patterns, results in predictable changes in expression of key genes and changes in anatomy. This finding suggests a hypothesis for the heretofore-mysterious observation that several channelopathies (diseases caused by mutations in ion channel genes such as KCNJ2) cause not only neurological deficits and cardiac arrhythmias but also craniofacial defects. The fact that these channels participate in the establishment of the normal bioelectric regionalization of the embryonic face may explain why channels are essential for craniofacial patterning. Our project aims to: 1) characterize in detail the bioelectric properties of the early face relative to gene expression domains (a physiomics atlas merging transcriptional and biophysical data);2) explore the emergence of the bioelectric face patterns by formulating a predictive mathematical model of self-organization within electrically-coupled cells;3) reveal molecular details of how voltage gradients regulate specific downstream face-patterning gene expression domains;and 4) develop optogenetic techniques to read/write desired electrical patterns in living tissue to override incorrect membrane voltage patterns thus preventing defects. The resulting data will: serve as an essential foundation for future attempts to merge biophysical and transcriptional regulatory layers in order to explain complex development;establish a quantitative model to prescribe minimally invasive corrective manipulations of voltage-dependent patterning;and to chart a new approach toward exploiting guided self-assembly of bioelectrical patterns to address issues in regenerative medicine, etiology and treatment of birth defects, as well as produce new hybrid constructs via synthetic bioengineering.

Public Health Relevance

Mutations in ion channel genes give rise to several syndromes with mispatterning of the face. We identified a novel aspect of craniofacial development - bioelectric signaling, which explains the origin of these birth defects. We will probe the mechanisms by which voltage gradients pattern the embryonic face and develop a roadmap for biomedical treatment of the channelopathies that affect the head and face.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CB-J (55))
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Mukhopadhyay, Mahua
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Tufts University
Schools of Arts and Sciences
United States
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