The integrity, or barrier function, of the intestinal epithelium is of paramount importance in -maintaining good health. This is largely imparted by a single layer of epithelial cells linked by the transmembrane tight junction protein complex near their apical surface. Disruption of epithelial permeability via the tight junctions can contribute to disease progression. The cytokine IFNγ is involved in many inflammatory processes and has been shown to dramatically increase permeability via changes at the tight junction in experimental models. One of its key effectors is the transcription factor, -IRF-1. In our studies of the role of IRF-1 in barrier function using the human T84 intestinal epithelial cell monolayer model, we have found that induction of IRF-1 alone is insufficient to change permeability and that if IRF-1 is involved in mediating the permeability effects of IFNγ, then other factors must also be required.

We conclude that intestinal crypt fission during infancy is mediated by Wnt signalling. It is possible that local treatment with Wnt agonists could be used to increase intestinal growth.

The epithelial tight junction forms a barrier to paracellular solute movement. In this study we show that the heterotrimeric G-protein Galpha13 regulates the epithelial tight junction barrier. We generated MDCKII kidney epithelial cell lines in which the expression of an active Galpha13 mutant (Galpha13Q226L) could be induced. We demonstrated that Galpha13Q226L expression increased paracellular permeability and caused the disruption and redistribution of proteins comprising the tight junction and the adherens junction away from sites of cell contact and the appearance of basal stress fibers. The effects on the junctional proteins and the actin cytoskeleton were abrogated by the Rho kinase inhibitor Y27632 but not by the Src kinase inhibitor PP2. The Galpha13 mediated increase in permeability was also Src kinase independent but was partly dependent on Rho kinase signalling. Our data establish a link between Galpha13, Rho kinase signaling and epithelial barrier function and not only demonstrate that Galpha13 regulates epithelial apical junction properties but that it does so via signaling pathways that are distinct from the closely related protein Galpha12.

We conclude that Notch signaling promotes crypt fission and growth of the intestine by maintaining low apoptosis of crypt cells.

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