The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Janet Rossant - One of the best experts on this subject based on the ideXlab platform.

  • the role of CDX2 as a lineage specific transcriptional repressor for pluripotent network during trophectoderm and inner cell mass specification
    bioRxiv, 2018
    Co-Authors: Daosheng Huang, Amy Ralston, Ping Yuan, Mikael Huss, Tapan Kumar Mistri, Luca Pinello, Huckhui Ng, Guocheng Yuan, Junfeng Ji, Janet Rossant
    Abstract:

    The first cellular differentiation event in mouse development leads to the formation of the blastocyst consisting of the inner cell mass (ICM) and an outer functional epithelium called trophectoderm(TE). The lineage specific transcription factor CDX2 is required for proper TE specification, where it promotes expression of TE genes, and represses expression of Pou5f1 (OCT4) by inhibiting OCT4 from promoting its own expression. However its downstream network in the developing early embryo is not fully characterized. Here, we performed high-throughput single embryo qPCR analysis in CDX2 null embryos to identify components of the CDX2-regulated network in vivo. To identify genes likely to be regulated by CDX2 directly, we performed CDX2 ChIP-Seq on trophoblast stem (TS) cells, derived from the TE. In addition, we examined the dynamics of gene expression changes using an inducible CDX2 embryonic stem (ES) cell system, so that we could predict which CDX2-bound genes are activated or repressed by CDX2 binding. By integrating these data with observations of chromatin modifications, we were able to identify novel regulatory elements that are likely to repress gene expression in a lineage-specific manner.Interestingly, we found CDX2 binding sites within regulatory elements of key pluripotent genes such as Pou5f1 and Nanog, pointing to the existence of a novel mechanism by which CDX2 maintains repression of OCT4 in trophoblast. Our study proposes a general mechanism in regulating lineage segregation during mammalian development.

  • the role of CDX2 as a lineage specific transcriptional repressor for pluripotent network during the first developmental cell lineage segregation
    Scientific Reports, 2017
    Co-Authors: Daosheng Huang, Amy Ralston, Ping Yuan, Mikael Huss, Tapan Kumar Mistri, Luca Pinello, Huckhui Ng, Guocheng Yuan, Junfeng Ji, Janet Rossant
    Abstract:

    The first cellular differentiation event in mouse development leads to the formation of the blastocyst consisting of the inner cell mass (ICM) and trophectoderm (TE). The transcription factor CDX2 is required for proper TE specification, where it promotes expression of TE genes, and represses expression of Pou5f1 (OCT4). However its downstream network in the developing embryo is not fully characterized. Here, we performed high-throughput single embryo qPCR analysis in CDX2 null embryos to identify CDX2-regulated targets in vivo. To identify genes likely to be regulated by CDX2 directly, we performed CDX2 ChIP-Seq on trophoblast stem (TS) cells. In addition, we examined the dynamics of gene expression changes using inducible CDX2 embryonic stem (ES) cells, so that we could predict which CDX2-bound genes are activated or repressed by CDX2 binding. By integrating these data with observations of chromatin modifications, we identify putative novel regulatory elements that repress gene expression in a lineage-specific manner. Interestingly, we found CDX2 binding sites within regulatory elements of key pluripotent genes such as Pou5f1 and Nanog, pointing to the existence of a novel mechanism by which CDX2 maintains repression of OCT4 in trophoblast. Our study proposes a general mechanism in regulating lineage segregation during mammalian development.

  • CDX2 acts downstream of cell polarization to cell-autonomously promote trophectoderm fate in the early mouse embryo.
    Developmental biology, 2007
    Co-Authors: Amy Ralston, Janet Rossant
    Abstract:

    The first lineage decision during mouse development is the establishment of trophectoderm and inner cell mass lineages, morphologically distinguishable at the blastocyst stage. The Caudal-like transcription factor CDX2 is required for repression of inner cell mass genes Oct4 and Nanog in the trophectoderm. Expression of CDX2 in the trophectoderm is thus one of the earliest known events in lineage determination. However, it is not clear whether the CDX2 expression pattern is the cause or the consequence of this first lineage decision. Here, we show that CDX2 is initially ubiquitously expressed, and becomes progressively upregulated in outside, future trophectoderm cells prior to blastocyst formation. Ubiquitous CDX2 expression begins around the time of cell polarization, but we show that cell polarization is independent of zygotic CDX2. Finally, we show functionally that CDX2 is downstream of lineage allocation since CDX2 mutant cells, which show cell-autonomous defects in expression of Oct4, Nanog, and the trophectoderm marker Eomesodermin, do not preferentially contribute to inner cell mass in chimeric blastocysts. CDX2 therefore appears to act downstream of the first lineage decision, suggesting that processes influencing lineage allocation or morphogenesis may regulate CDX2 expression along the inside/outside axis of the embryo.

Aud Svindland - One of the best experts on this subject based on the ideXlab platform.

  • prognostic predictive and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer
    Molecular Oncology, 2018
    Co-Authors: Jarle Bruun, Anita Sveen, Rita Barros, Peter W Eide, Ina Andrassy Eilertsen, Matthias Kolberg, Teijo Pellinen, Leonor David, Aud Svindland
    Abstract:

    We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I-IV primary CRCs by gene expression (n = 403) or immunohistochemistry (n = 642) and in relation to 5-year relapse-free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I-III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF-mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III, the 5-year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2-negative cell lines were significantly more sensitive to chemotherapeutics than CDX2-positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2-negative cells and in patient tumors. Loss of CDX2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III. Early-stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX2 and mutated BRAF.

John P Lynch - One of the best experts on this subject based on the ideXlab platform.

  • intestine specific transcription factor CDX2 induces e cadherin function by enhancing the trafficking of e cadherin to the cell membrane
    American Journal of Physiology-gastrointestinal and Liver Physiology, 2010
    Co-Authors: Shinsuke Funakoshi, Duyen T Dang, Jianping Kong, Mary Ann S Crissey, Long H Dang, John P Lynch
    Abstract:

    CDX2 is an intestine-specific transcription factor required for normal intestinal epithelium development. CDX2 regulates the expression of intestine-specific genes and induces cell adhesion and columnar morphogenesis. CDX2 also has tumor-suppressor properties, including the reduction of colon cancer cell proliferation and cell invasion, the latter due to its effects on cell adhesion. E-cadherin is a cell adhesion protein required for adherens junction formation and the establishment of intestinal cell polarity. The objective of this study was to elucidate the mechanism by which CDX2 regulates E-cadherin function. Two colon cancer cell lines were identified in which CDX2 expression was associated with increased cell-cell adhesion and diminished cell migration. In both cell lines, CDX2 did not directly alter E-cadherin levels but increased its trafficking to the cell membrane compartment. CDX2 enhanced this trafficking by altering receptor tyrosine kinase (RTK) activity. CDX2 expression diminished phosphorylated Abl and phosphorylated Rac levels, which are downstream effectors of RTKs. Specific chemical inhibition or short interfering RNA (shRNA) knockdown of c-Abl kinase phenocopied CDX2's cell-cell adhesion effects. In Colo 205 cells, CDX2 reduced PDGF receptor and IGF-I receptor activation. This was mediated by caveolin-1, which was induced by CDX2. Targeted shRNA knockdown of caveolin-1 restored PDGF receptor and reversed E-cadherin membrane trafficking, despite CDX2 expression. We conclude that CDX2 regulates E-cadherin function indirectly by disrupting RTK activity and enhancing E-cadherin trafficking to the cell membrane compartment. This novel mechanism advances CDX2's prodifferentiation and antitumor properties and suggests that CDX2 may broadly regulate RTK activity in normal intestinal epithelium by modulating membrane trafficking of proteins.

  • the intestine specific transcription factor CDX2 inhibits β catenin tcf transcriptional activity by disrupting the β catenin tcf protein complex
    Carcinogenesis, 2010
    Co-Authors: Rong-jun Guo, Jianping Kong, Shinsuke Funakoshi, Hannah H. Lee, John P Lynch
    Abstract:

    CDX2 is an intestine-specific transcription factor known to regulate proliferation and differentiation. We have reported previously that CDX2 limits the proliferation of human colon cancer cells by inhibiting the transcriptional activity of the beta-catenin-T-cell factor (TCF) bipartite complex. Herein we further elucidate this mechanism. Studies with a classic CDX2 target gene and a canonical Wnt/beta-catenin/TCF reporter suggest that CDX2 regulates these promoters by distinctly different processes. Specifically, inhibition of beta-catenin/TCF activity by CDX2 does not require CDX2 transcriptional activity. Instead, CDX2 binds beta-catenin and disrupts its interaction with the DNA-binding TCF factors, thereby silencing beta-catenin/TCF target gene expression. Using CDX2 mutants, we map the CDX2 domains required for the inhibition of beta-catenin/TCF activity. We identify a subdomain in the N-terminus that is highly conserved and when mutated significantly reduces CDX2 inhibition of beta-catenin/TCF transcriptional activity. Mutation of this subdomain also abrogates CDX2's anti-proliferative effects in colon cancer cells. In summary, we conclude that CDX2 binds beta-catenin and disrupts the beta-catenin-TCF complex. Considering the pivotal role of beta-catenin/TCF activity in driving proliferation of normal intestinal epithelial and colon cancer cells, our findings suggest a novel mechanism for CDX2-mediated regulation of Wnt/beta-catenin signaling and cell proliferation.

Ramesh A. Shivdasani - One of the best experts on this subject based on the ideXlab platform.

  • The lineage-specific transcription factor CDX2 navigates dynamic chromatin to control distinct stages of intestine development.
    Development (Cambridge England), 2019
    Co-Authors: Namit Kumar, Yu Hwai Tsai, Lei Chen, Anbo Zhou, Kushal K. Banerjee, Madhurima Saxena, Sha Huang, Jinchuan Xing, Natalie H. Toke, Ramesh A. Shivdasani
    Abstract:

    Lineage-restricted transcription factors, such as the intestine-specifying factor CDX2, often have dual requirements across developmental time. Embryonic loss of CDX2 triggers homeotic transformation of intestinal fate, whereas adult-onset loss compromises crucial physiological functions but preserves intestinal identity. It is unclear how such diverse requirements are executed across the developmental continuum. Using primary and engineered human tissues, mouse genetics, and a multi-omics approach, we demonstrate that divergent CDX2 loss-of-function phenotypes in embryonic versus adult intestines correspond to divergent CDX2 chromatin-binding profiles in embryonic versus adult stages. CDX2 binds and activates distinct target genes in developing versus adult mouse and human intestinal cells. We find that temporal shifts in chromatin accessibility correspond to these context-specific CDX2 activities. Thus, CDX2 is not sufficient to activate a mature intestinal program; rather, CDX2 responds to its environment, targeting stage-specific genes to contribute to either intestinal patterning or mature intestinal function. This study provides insights into the mechanisms through which lineage-specific regulatory factors achieve divergent functions over developmental time.

  • The Lineage-Specific Transcription Factor CDX2 Navigates Dynamic Chromatin to Control Distinct Stages of Intestine Development
    2018
    Co-Authors: Namit Kumar, Ramesh A. Shivdasani, Yu Hwai Tsai, Lei Chen, Anbo Zhou, Kushal K. Banerjee, Madhurima Saxena, Sha Huang, Jinchuan Xing, Jason R. Spence
    Abstract:

    Lineage-restricted transcription factors, such as the intestine-specifying factor CDX2, often have dual requirements across developmental time. Embryonic-loss of CDX2 triggers homeotic transformation of intestinal fate, while adult-onset CDX2-loss compromises critical physiological functions but preserves intestinal identity. It is unclear how such diverse requirements are executed across the developmental continuum. Using primary and engineered human tissues, mouse genetics, and a multi-omics approach, we demonstrate that divergent CDX2 loss-of-function phenotypes in embryonic versus adult intestines correspond to divergent CDX2 chromatin-binding profiles in embryonic versus adult stages. CDX2 binds and activates distinct target genes in developing versus adult mouse and human intestinal cells. We find that temporal shifts in chromatin accessibility correspond to these context-specific CDX2 activities. Thus, CDX2 is not sufficient to activate a mature intestinal program, but rather, CDX2 responds to its environment, targeting stage-specific genes to contribute to either intestinal patterning or maturity. This study provides insights into the mechanisms through which lineage-specific regulatory factors achieve divergent functions over developmental time.

  • distinct processes and transcriptional targets underlie CDX2 requirements in intestinal stem cells and differentiated villus cells
    Stem cell reports, 2015
    Co-Authors: Adrianna San K Roman, Ramesh A. Shivdasani, Alessio Tovaglieri, David T Breault
    Abstract:

    Lgr5-expressing intestinal stem cells (ISCs) renew the adult gut epithelium by producing mature villus cells (VCs); the transcriptional basis for ISC functions remains unclear. RNA sequencing analysis identified transcripts modulated during differentiation of Lgr5+ ISCs into VCs, with high expression of the intestine-restricted transcription factor (TF) gene CDX2 in both populations. CDX2-deleted mouse ISCs showed impaired proliferation and long-term inability to produce mature lineages, revealing essential ISC functions. Chromatin immunoprecipitation sequencing analysis of CDX2 in Lgr5+ ISCs, coupled with mRNA profiling of control and CDX2−/− ISCs, identified features of CDX2 regulation distinct from VCs. Most CDX2 binding in ISCs occurs in anticipation of future gene expression, but whereas CDX2 primarily activates VC genes, direct ISC targets are activated and repressed. Diverse CDX2 requirements in stem and differentiated cells may reflect the versatility of TFs that specify a tissue in development and control the same tissue in adults.

Pierre Laurentpuig - One of the best experts on this subject based on the ideXlab platform.

  • CDX2 prognostic value in stage ii iii resected colon cancer is related to cms classification
    Annals of Oncology, 2017
    Co-Authors: Camilla Pilati, Julien Taieb, Ralyath Balogoun, Laetitia Marisa, A De Reynies, Pierre Laurentpuig
    Abstract:

    Background Caudal-type homeobox transcription factor 2 (CDX2) is involved in colon cancer (CC) oncogenesis and has been proposed as a prognostic biomarker in patients with stage II or III CC. Patients and methods We analyzed CDX2 expression in a series of 469 CC typed for the new international consensus molecular subtype (CMS) classification, and we confirmed results in a series of 90 CC. Results Here, we show that lack of CDX2 expression is only present in the mesenchymal subgroup (CMS4) and in MSI-immune tumors (CMS1) and not in CMS2 and CMS3 colon cancer. Although CDX2 expression was a globally independent prognostic factor, loss of CDX2 expression is not associated with a worse prognosis in the CMS1 group, but is highly prognostic in CMS4 patients for both relapse free and overall survival. Similarly, lack of CDX2 expression was a bad prognostic factor in MSS patients, but not in MSI. Conclusions Our work suggests that combination of the consensual CMS classification and lack of CDX2 expression could be a useful marker to identify CMS4/CDX2-negative patients with a very poor prognosis.