Gap junctions are membrane specializations that contain clusters of intercellular channels that allow direct passage of ions and molecules up to 1000 Da between cells. Each gap junction channel is formed by the coaxial alignment of two hemi-channels, or connexons. Each connexon is an oligomeric assembly of a family of related proteins called connexins (Cx). Most connexins are phosphoproteins. This modification has been implicated in trafficking, assembly, insertion into the plasma membrane, gating, internalization and degradation. Because of their permeability properties, gap junctions may allow formation of functional syncytia between heterogeneous cells. The importance of gap junction communication in different tissues has been emphasized by the recent findings of mutant connexins linked to several human diseases. These include mutations in Cx32 in X-linked Charcot-Marie-Tooth disease, mutations in Cx26 and Cx31 in hereditary non-syndromic deafness, mutations in Cx26 in skin disease, mutations of Cx43 in craniofacial and limb dysmorphisms, and mutations of Cx50 and Cx46 in inherited congenital cataracts.

Regulation of gap junctions can occur at different steps of the connexin/gap junction biosynthetic/degradative pathway (e.g., when the connexin is in its monomeric or hexameric form, or when it is part of a gap junction channel or plaque). I am using diverse systems to study different aspects of the regulation of gap junctions made of different connexins. The current projects can be summarized as follows:

I. Regulation of gap junctions during development

The developmental program that gives rise to an organism from relatively equivalent cells is still intriguing. It has been hypothesized that the formation of communication compartments is involved in this phenomenon by allowing cells to take on different fates. Because gap junctions are likely involved in the formation of communication compartments, one of the projects is aimed at studying the role of gap junctions during development. This project involves the study of the patterns of connexin expression during normal development of the chicken embryo to define the connexins expressed in different communication compartments and how their pattern of expression changes with cell differentiation/specification, and to study how perturbations in the extent of the communication compartments (by over-expression or knock-out of a connexin subtype) affects development.

II. Regulation of lens gap junctions.

The lens is an avascular organ in which gap junctions play a pivotal role for intercellular transfer of ions and metabolites and thus for maintenance of lens transparency. This project involves characterization of the functional and cellular behavior of wild type and mutant lens-specific connexins linked to congenital cataracts. These studies are aimed at finding the mechanism(s) by which the mutant connexin induces the cataractous phenotype, and to determine in mouse models the effects of malfunction of gap junctions on development of the lens and surrounding tissues.