OHSU

Linda Musil, PhD

Linda Musil, PhD

Folding, transport, assembly, and degradation of gap junction proteins; regulation of lens development and function by growth factors

Gap junctions are aggregations of intercellular channels that mediate the regulated transfer of ions and small molecules between adjoining cells. Present in virtually all animal cells, gap junctions serve to maintain metabolic continuity within, and relay signals between, adjacent cells. In this capacity, gap junctions are essential to the proper function of tissues throughout the body and are involved in the regulation of cellular differentiation, growth control, and embryonic development. Our lab combines biochemical and molecular biology approaches to study gap junction formation and function using both wild-type and disease-causing mutant forms of gap junction proteins (connexins). Our current emphasis is on the processes of gap junction assembly and degradation, both of which are highly regulated and have several unexpected features. For example, we have shown that a large fraction of newly synthesized, wild-type connexins are degraded shortly after synthesis via ERAD (ER-associated degradation). Induction of the cytosolic heat shock response by mild oxidative or thermal stress inhibits this process, leading to a large increase in gap junction formation and function in otherwise gap junction-deficient cell types (VanSlyke and Musil 2002 J. Cell Biol.,157:381-394; selected as an Editors' Choice in Science, 296:1209-1210). A related interest is elucidating the signal transduction pathways whereby gap junctions influence, and are influenced by, other molecules, especially growth factors. One of the systems that we study is the vertebrate lens, an avascular organ that is uniquely dependent on gap junctions to maintain the metabolic homeostasis required for lens transparency (Le and Musil 2001 J. Cell Biol. 154:197-216). The goal of these studies is to understand how gap junction-mediated cell-cell communication is established and how gap junction assembly and degradation (and therefore function) are modulated in physiological and pathophysiological processes as diverse as parturition, early embryonic development, cataract, the peripheral neuropathy X-linked Charcot-Marie-Tooth disease, oxidative stress, and cancer.

 

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