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¹ Department of Cell Biology, University of Geneva, 1211 Geneva, Switzerland
² Division of Cell Biology, Institute of Ophthalmology, University College London, EC1V 9EL London, UK
³ Department of Physiology, Center for Research and Advanced Studies, Mexico, D.F., 07360 Mexico
⁴ Division of Cell Sciences, School of Biological Sciences, University of Southampton, SO16 7PX Southampton, UK
⁵ Curie Institute, Research Section, Paris 7505, France

Address correspondence to Karl Matter, Div. of Cell Biology, Institute of Ophthalmology, University College London, Bath St., London EC1V 9EL, UK. Tel.: 44-20-7608-4014. Fax: 44-20-7608-4034. E-mail: k.matter{at}ucl.ac.uk; or Maria S. Balda, Div. of Cell Biology, Institute of Ophthalmology, University College London, Bath St., London EC1V 9EL, UK. Tel.: 44-20-7608-4014. Fax: 44-20-7608-4034. E-mail: m.balda{at}ucl.ac.uk

Rho family GTPases are important regulators of epithelial tight junctions (TJs); however, little is known about how the GTPases themselves are controlled during TJ assembly and function. We have identified and cloned a canine guanine nucleotide exchange factor (GEF) of the Dbl family of proto-oncogenes that activates Rho and associates with TJs. Based on sequence similarity searches and immunological and functional data, this protein is the canine homologue of human GEF-H1 and mouse Lfc, two previously identified Rho-specific exchange factors known to associate with microtubules in nonpolarized cells. In agreement with these observations, immunofluorescence of proliferating MDCK cells revealed that the endogenous canine GEF-H1/Lfc associates with mitotic spindles. Functional analysis based on overexpression and RNA interference in polarized MDCK cells revealed that this exchange factor for Rho regulates paracellular permeability of small hydrophilic tracers. Although overexpression resulted in increased size-selective paracellular permeability, such cell lines exhibited a normal overall morphology and formed fully assembled TJs as determined by measuring transepithelial resistance and by immunofluorescence and freeze-fracture analysis. These data indicate that GEF-H1/Lfc is a component of TJs and functions in the regulation of epithelial permeability.

Key Words: epithelia; Dbl; intercellular adhesion; actin; microtubules

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