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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; ∼80 villi/mouse) and crypt depth (black bracket; ∼800 open crypts/mouse). KaisoTg/+ display increased crypt depth compared to their Non-Tg siblings, p = 0.001. (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, p = 0.014. (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, p = 0.011 & 0.002. (B) Lysozyme staining revealed increased Paneth cell numbers in KaisoTg/+ mice, p = 0.017. (C) Synaptophysin positive enteroendocrine cells (arrowheads) are increased in KaisoTg/+ mice, p = 0.031. n = 3 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 Kaiso’s 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.
Blattler,
ZBTB33 binds unmethylated regions of the genome associated with actively expressed genes.
2013, Pubmed
Blattler,
ZBTB33 binds unmethylated regions of the genome associated with actively expressed genes.
2013,
Pubmed Cofre,
Knock-down of Kaiso induces proliferation and blocks granulocytic differentiation in blast crisis of chronic myeloid leukemia.
2012,
Pubmed Dai,
Kaiso is expressed in lung cancer: its expression and localization is affected by p120ctn.
2010,
Pubmed Dai,
Cytoplasmic Kaiso is associated with poor prognosis in non-small cell lung cancer.
2009,
Pubmed Daniel,
Dancing in and out of the nucleus: p120(ctn) and the transcription factor Kaiso.
2007,
Pubmed Daniel,
The p120(ctn)-binding partner Kaiso is a bi-modal DNA-binding protein that recognizes both a sequence-specific consensus and methylated CpG dinucleotides.
2002,
Pubmed Donaldson,
Kaiso represses the cell cycle gene cyclin D1 via sequence-specific and methyl-CpG-dependent mechanisms.
2012,
Pubmed Filion,
A family of human zinc finger proteins that bind methylated DNA and repress transcription.
2006,
Pubmed Goldstein,
Isolated ileal erosions in patients with mildly altered bowel habits. A follow-up study of 28 patients.
2006,
Pubmed Iioka,
Kaiso is a bimodal modulator for Wnt/beta-catenin signaling.
2009,
Pubmed
,
Xenbase Jacques,
Joint expedition: linking gut inflammation to arthritis.
2008,
Pubmed Jensen,
Control of endodermal endocrine development by Hes-1.
2000,
Pubmed Jiang,
P120-catenin isoforms 1 and 3 regulate proliferation and cell cycle of lung cancer cells via β-catenin and Kaiso respectively.
2012,
Pubmed Jones,
Nuclear Kaiso indicates aggressive prostate cancers and promotes migration and invasiveness of prostate cancer cells.
2012,
Pubmed Kuhnert,
Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1.
2004,
Pubmed Lopes,
Kaiso contributes to DNA methylation-dependent silencing of tumor suppressor genes in colon cancer cell lines.
2008,
Pubmed Martín Caballero,
The methyl-CpG binding proteins Mecp2, Mbd2 and Kaiso are dispensable for mouse embryogenesis, but play a redundant function in neural differentiation.
2009,
Pubmed Milano,
Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation.
2004,
Pubmed Ogaki,
Wnt and Notch signals guide embryonic stem cell differentiation into the intestinal lineages.
2013,
Pubmed Okamoto,
Requirement of Notch activation during regeneration of the intestinal epithelia.
2009,
Pubmed Ostanin,
T cell-induced inflammation of the small and large intestine in immunodeficient mice.
2006,
Pubmed Park,
Kaiso/p120-catenin and TCF/beta-catenin complexes coordinately regulate canonical Wnt gene targets.
2005,
Pubmed
,
Xenbase Park,
Frodo links Dishevelled to the p120-catenin/Kaiso pathway: distinct catenin subfamilies promote Wnt signals.
2006,
Pubmed
,
Xenbase Pinto,
Regulatory sequences of the mouse villin gene that efficiently drive transgenic expression in immature and differentiated epithelial cells of small and large intestines.
1999,
Pubmed Prokhortchouk,
The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor.
2001,
Pubmed Prokhortchouk,
Kaiso-deficient mice show resistance to intestinal cancer.
2006,
Pubmed
,
Xenbase Rubin,
Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer.
2012,
Pubmed Ruzov,
Kaiso is a genome-wide repressor of transcription that is essential for amphibian development.
2004,
Pubmed
,
Xenbase Ruzov,
The interaction of xKaiso with xTcf3: a revised model for integration of epigenetic and Wnt signalling pathways.
2009,
Pubmed
,
Xenbase Ruzov,
The non-methylated DNA-binding function of Kaiso is not required in early Xenopus laevis development.
2009,
Pubmed
,
Xenbase Saleh,
Innate immune mechanisms of colitis and colitis-associated colorectal cancer.
2011,
Pubmed Sasai,
Sequence-specific recognition of methylated DNA by human zinc-finger proteins.
2010,
Pubmed Smalley-Freed,
p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice.
2010,
Pubmed Smalley-Freed,
Adenoma formation following limited ablation of p120-catenin in the mouse intestine.
2011,
Pubmed Spring,
The catenin p120ctn inhibits Kaiso-mediated transcriptional repression of the beta-catenin/TCF target gene matrilysin.
2005,
Pubmed Terzić,
Inflammation and colon cancer.
2010,
Pubmed VanDussen,
Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells.
2012,
Pubmed van Roy,
A role for Kaiso-p120ctn complexes in cancer?
2005,
Pubmed
,
Xenbase Vermeulen,
Nuclear Kaiso expression is associated with high grade and triple-negative invasive breast cancer.
2012,
Pubmed Wang,
Expression of P120 catenin, Kaiso, and metastasis tumor antigen-2 in thymomas.
2012,
Pubmed Xavier,
Unravelling the pathogenesis of inflammatory bowel disease.
2007,
Pubmed Yang,
Differential regulation of D-type cyclins in the mouse intestine.
2006,
Pubmed Yoon,
N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso.
2003,
Pubmed Zecchini,
Notch signaling regulates the differentiation of post-mitotic intestinal epithelial cells.
2005,
Pubmed
