DECREASED GASTROINTESTINAL TRANSIT TIME IN MICE EXPRESSING A MUTANT PERIPHERIN

Abstract

63 Peripherin is a type III intermediate filament (IF) protein that is expressed mainly in peripheral neurons, including those of the enteric nervous system (ENS). Although its structure and distribution have been studied in detail, its precise function remains elusive. Since the ENS plays a major role in gut motility, we carried out preliminary experiments to test the hypothesis that disruption of the IF cytoskeleton in peripheral neurons has an effect on gastrointestinal transit. Transgenic mice that express a mutant peripherin protein were generated using a dominant negative strategy. These mice were indistinguishable from their non-transgenic littermates with regards to size and viability. Immunocytochemical analysis with peripherin antibodies showed disruption of IF into globular structures within neuronal cell bodies. Mice carrying the mutant peripherin protein (n=8) and their wild type littermate controls (n=10) were studied at seven weeks of age. Gross morphological and histological comparisions of the gastrointestinal tract indicated no obvious differences between the two groups. Gastrointestinal transit time was determined by the time required for barium to travel from the stomach to the rectum, using serial x-rays. These studies revealed a statistically significant decrease in gastrointestinal transit time in mutant peripherin-expressing mice. Peptides that facilitate (tachykinins) and inhibit gastrointestinal motility have been shown to be produced by enteric neurons. We propose that disruption of the neuronal IF cytoskeleton results in an altered release of peptides from the affected neurons eventually leading to enhanced tachykinin activity. Studies aimed at investigating this functional role for peripherin are underway.