Wound healing is essential for maintaining the integrity of multicellular organisms. In every species studied, disruption of an epithelial layer instantaneously generates endogenous electric fields, which have been proposed to be important in wound healing^{1, 2, 3}. The identity of signalling pathways that guide both cell migration to electric cues and electric-field-induced wound healing have not been elucidated at a genetic level. Here we show that electric fields, of a strength equal to those detected endogenously, direct cell migration during wound healing as a prime directional cue. Manipulation of endogenous wound electric fields affects wound healing in vivo. Electric stimulation triggers activation of Src and inositol–phospholipid signalling, which polarizes in the direction of cell migration. Notably, genetic disruption of phosphatidylinositol-3-OH kinase- (PI(3)K) decreases electric-field-induced signalling and abolishes directed movements of healing epithelium in response to electric signals. Deletion of the tumour suppressor phosphatase and tensin homolog (PTEN) enhances signalling and electrotactic responses. These data identify genes essential for electrical-signal-induced wound healing and show that PI(3)K and PTEN control electrotaxis.

1. School of Medical Sciences and Department of Ophthalmology, University of Aberdeen, Aberdeen AB25 2ZD, UK
2. Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr Bohr-Gasse 3, A-1030 Vienna, Austria
3. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143, USA
4. Department of Pathology and Immunology, and
5. Department of Molecular Biology, Akita University School of Medicine, 1-1-1 Hondo, 010-8543 Akita, Japan
6. Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
7. †Present address: Department of Cell and Developmental Biology, University of Illinois, B107 Chemical and Life Sciences Laboratory, 601 S. Goodwin Avenue, Urbana, Illinois 61801, USA

Correspondence to: Min Zhao¹Josef M. Penninger² Correspondence and requests for materials should be addressed to M.Z. (Email: m.zhao@abdn.ac.uk) or J.M.P (Email: josef.penninger@imba.oeaw.ac.at).

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