
<ArticleTitle>Extranuclear sequestration of <prot>phospho-Jun N-terminal kinase</prot> and distorted villi produced by activated <prot>Rac1</prot> in the intestinal epithelium of chimeric mice.</ArticleTitle>
<AbstractText>Previously, we used a genetic mosaic system to conduct an in vivo analysis of the effects of <prot>Rac1</prot> activation on the developing intestinal epithelium ( Stappenbeck, T. S. and Gordon, J. I. (2000) Development 127, 2629-2642). Expression of a constitutively active human <prot>Rac1</prot> (<prot>Rac1Leu61</prot>) in the 129/Sv-derived small intestinal epithelium of C57Bl/6-ROSA26&#60;--129/Sv chimeric mice led to precocious differentiation of some lineages with accompanying alterations in their apical actin. We have now explored the underlying mechanisms. <prot>Rac1Leu61</prot> leads to accumulation of the 46 kDa form of <prot>phosphorylated Jun N-terminal kinase</prot> (<prot>p-Jnk</prot>) in the apical cytoplasm, but not in the nucleus of E18.5 proliferating and differentiating intestinal epithelial cells. The effect is cell-autonomous, selective for this mitogen-activated protein kinase family member, and accompanied by apical cytoplasmic accumulation of <prot>p21</prot>-activated kinase. <prot>c-Jun</prot>, a downstream nuclear target of <prot>p-Jnk</prot>, does not show evidence of enhanced phosphorylation, providing functional evidence for cytoplasmic sequestration of <prot>p-Jnk</prot> in <prot>Rac1Leu61</prot>-expressing epithelium. In adult chimeras, <prot>Rac1</prot> activation augments cell proliferation in crypts of Lieberkühn, without a compensatory change in basal apoptosis and produces a dramatic, very unusual widening of villi. These results reveal a novel in vivo paradigm for <prot>Rac1</prot> activation involving <prot>p-Jnk</prot>-mediated signaling at a distinctive extra-nuclear site, with associated alterations in the actin cytoskeleton. They also provide a new perspective about the determinants of small intestinal villus morphogenesis.</AbstractText>
