Abstract
Since its discovery, several studies have implicated the POZ-ZF protein Kaiso in both developmental and tumorigenic processes. However, most of the information regarding Kaiso’s function to date has been gleaned from studies in Xenopus laevis embryos and mammalian cultured cells. To examine Kaiso’s role in a relevant, mammalian organ-specific context, we generated and characterized a Kaiso transgenic mouse expressing a murine Kaiso transgene under the control of the intestine-specific villin promoter. Kaiso transgenic mice were viable and fertile but pathological examination of the small intestine revealed distinct morphological changes. Kaiso transgenics (KaisoTg/+) exhibited a crypt expansion phenotype that was accompanied by increased differentiation of epithelial progenitor cells into secretory cell lineages; this was evidenced by increased cell populations expressing Goblet, Paneth and enteroendocrine markers. Paradoxically however, enhanced differentiation in KaisoTg/+ was accompanied by reduced proliferation, a phenotype reminiscent of Notch inhibition. Indeed, expression of the Notch signalling target HES-1 was decreased in KaisoTg/+ animals. Finally, our Kaiso transgenics exhibited several hallmarks of inflammation, including increased neutrophil infiltration and activation, villi fusion and crypt hyperplasia. Interestingly, the Kaiso binding partner and emerging anti-inflammatory mediator p120ctn is recruited to the nucleus in KaisoTg/+ mice intestinal cells suggesting that Kaiso may elicit inflammation by antagonizing p120ctn function.
Highlights
Since its discovery as a binding partner for the Src kinase substrate and cell adhesion protein p120ctn, mounting evidence suggests that the POZ-ZF transcription factor Kaiso functions in vertebrate development and tumorigenesis [1,2,3,4,5,6,7,8]
Since pronuclear injections result in random genome integration, transgene copy number was estimated by polymerase chain reaction (PCR) (Figure 1B)
Kaiso was expressed along the entire crypt-villus axis with the most robust expression in the villi, which is consistent with the normal expression pattern of villin [30]
Summary
Since its discovery as a binding partner for the Src kinase substrate and cell adhesion protein p120ctn, mounting evidence suggests that the POZ-ZF transcription factor Kaiso functions in vertebrate development and tumorigenesis [1,2,3,4,5,6,7,8]. One study investigated the effect of Kaiso depletion on murine development and found that Kaiso null mice exhibited no overt developmental phenotypes [8]. This unexpected lack of a developmental phenotype may be attributed to the existence of two Kaiso-like proteins in mammals, ZBTB4 and ZBTB38, that may function redundantly with Kaiso [16,20], and highlights what may be an important consideration in deciphering Kaiso’s role in mammalian systems. Given that constitutive Wnt signalling resulting from mutation of APC functions as the first ‘‘hit’’ in ApcMin/+-mediated tumorigenesis, the Kaiso-null/ApcMin/+
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