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Chaudhary R
,
Pierre CC
,
Nanan K
,
Wojtal D
,
Morone S
,
Pinelli C
,
Wood GA
,
Robine S
,
Daniel JM
.
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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 (Kaiso(Tg/+)) 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 Kaiso(Tg/+) was accompanied by reduced proliferation, a phenotype reminiscent of Notch inhibition. Indeed, expression of the Notch signalling target HES-1 was decreased in Kaiso(Tg/+) 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 p120(ctn) is recruited to the nucleus in Kaiso(Tg/+) mice intestinal cells suggesting that Kaiso may elicit inflammation by antagonizing p120(ctn) function.
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Figure 2. Subcellular localization and expression of ectopic Kaiso in Line A KaisoTg/+ small intestines.KaisoTg/+ mice display strong nuclear Kaiso in the villi and crypt cells, compared to non-transgenic mice (Non-Tg), which mainly display weak Kaiso staining in the cytoplasm. Additionally, KaisoTg/+ mice display strong nuclear c-Myc staining corresponding to ectopic myc-tagged Kaiso expression, while Non-Tg mice display cytoplasmic c-Myc expression.
Figure 3. Kaiso transgenic mice exhibit inflammation of the intestinal mucosa.(A) Hematoxylin and eosin (H&E) stained sections were used to measure villi length (red bracket; â¼80 villi/mouse) and crypt depth (black bracket; â¼800 open crypts/mouse). KaisoTg/+ display increased crypt depth compared to their Non-Tg siblings, pâ=â0.001. (B) KaisoTg/+ mice exhibit increased immune cell infiltration of the lamina propria (yellow demarcated area) accompanied by increased MPO activity compared to their Non-Tg siblings, pâ=â0.014. (C) Line B mice do not exhibit immune cell infiltration or enhanced MPO activity compared to Non-Tg siblings. ** represents significance.
Figure 4. KaisoTg/+ mice display nuclear p120ctn in villi of the small intestine.Immunofluorescence staining for p120ctn showed nuclear localization of p120ctn in epithelial cells of villi overexpressing Kaiso (KaisoTg/+), while Non-Tg mice displayed membrane localized p120ctn.
Figure 5. Secretory cell lineages are expanded in the intestines of KaisoTg/+ mice.(A) PAS stain for Goblet cells (black arrowheads) revealed increased numbers of Goblet cells in both the villi and crypts of KaisoTg/+ intestines, pâ=â0.011 & 0.002. (B) Lysozyme staining revealed increased Paneth cell numbers in KaisoTg/+ mice, pâ=â0.017. (C) Synaptophysin positive enteroendocrine cells (arrowheads) are increased in KaisoTg/+ mice, pâ=â0.031. nâ=â3 mice/genotype; measurements performed by two independent blind observers; T-test used for p-value. ** represents significance.
Figure 6. Cell proliferation is decreased in KaisoTg/+ mice.Cell proliferation was evaluated by Ki67 (A) and Cyclin D1 (B) staining. Both markers exhibited reduced staining in KaisoTg/+ mice compared to their Non-Tg siblings. Reduced CyclinD1 expression was also confirmed by immunoblot analysis of 3 different mice intestines (C). ** represents significance.
Figure 7. KaisoTg/+ mice display decreased HES-1 expression in the small intestine.Both Non-Tg and KaisoTg/+ tissues displayed nuclear HES-1 expression in the crypts of the small intestine, however KaisoTg/+ tissue displays significantly decreased HES-1 expression in the villi. Quantitative RT-PCR showed a significant decrease in HES-1 expression in KaisoTg/+ mice. Values were first normalized to the GAPDH housekeeping gene, followed by normalizing to non-Tg HES-1 expression (** represents p<0.05).
Figure 8. Schematic model of Kaisoâs postulated effects in the intestine.Notch signalling in the crypts modulates differentiation of progenitor cells into the various epithelial cell lineages: enterocytes, Goblet, Paneth and enteroendocrine (EEC) cells. The gradient of Notch signaling is indicated by the grey triangle. HES-1 is necessary for the proper specification of these cell types. p120ctn localizes to the membrane in the enterocytes of Non-Tg mice (green-membraned cells), but is recruited to the nucleus in KaisoTg/+ mice (green nucleated cells), which inhibits Notch signaling and Hes-1 expression, thus inducing inflammation.
Figure 1. Generation of transgenic mouse lines ectopically expressing villin-Kaiso.(A) Myc-tagged murine Kaiso cDNA was cloned downstream of the 9 kb villin promoter sequence. (B) The transgene copy number in each transgenic line was evaluated via PCR. Line A transgenic animals have the greatest copy number. (C) RT-PCR confirmed expression of the Kaiso transgene in villin-expressing tissues of transgenic mice, i.e. the small intestine, large intestine, and kidneys. (D) Immunoblot analysis shows increased Kaiso expression in both small and large intestines in Kaiso transgenic (KaisoTg
/+) Line A mice compared to non-transgenic (Non-Tg) siblings.
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