Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression
Open accessAbstract
Although the T-box family of transcription factors function in many different tissues, their role in liver development is unknown. Here we show that Tbx3, the T-box gene that is mutated in human ulnar-mammary syndrome, is specifically expressed in multipotent hepatic progenitor cells,`hepatoblasts', isolated from the developing mouse liver. Tbx3-deficient hepatoblasts presented severe defects in proliferation as well as uncontrollable hepatobiliary lineage segregation, including the promotion of cholangiocyte (biliary epithelial cell) differentiation, which thereby caused abnormal liver development. Deletion of Tbx3 resulted in the increased expression of the tumor suppressor p19ARF(Cdkn2a), which in turn induced a growth arrest in hepatoblasts and activated a program of cholangiocyte differentiation. Thus, Tbx3 plays a crucial role in controlling hepatoblast proliferation and cell-fate determination by suppressing p19ARF expression and thereby promoting liver organogenesis.
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Written from the paper’s full text.
TL;DR
Tbx3 is specifically expressed in multipotent mouse hepatoblasts and is required for their proliferation and hepatobiliary lineage segregation. Tbx3 acts by repressing p19ARF; loss of Tbx3 increases p19ARF, causing growth arrest and promoting cholangiocyte differentiation.
Key findings
- Tbx3 expression was restricted to c-Met+ c-Kit− CD45− Ter119− hepatic epithelial cells/hepatoblasts in E13.5 mouse liver; among T-box genes tested, only Tbx3 was expressed in this population.
- Tbx3−/− embryonic livers were much smaller, with reduced BrdU-incorporating and PCNA+ proliferating cells but no increase in apoptosis; PCNA+ cells among Hnf4α+ cells were 68.8% in wild-type versus 27.3% in Tbx3−/− livers.
- Clonal culture of c-Met+ c-Kit− CD45− Ter119− cells showed impaired colony formation in Tbx3−/− cells; after 18 days, wild-type colonies contained ~25% Alb+ hepatocytes and ~60% CK7+ cholangiocytes, whereas Tbx3−/− colonies were 95% CK7+ cholangiocytes and only ~2% Alb+ hepatocytes.
- Tbx3−/− liver cells upregulated p19ARF and p21WAF1/CIP1; restoring Tbx3 decreased p19ARF, and p19ARF-siRNA partially rescued proliferation of Tbx3-shRNA-expressing hepatoblast progeny. p19ARF overexpression reduced proliferation and increased CK19/CK7 expression and CK7+ cholangiocytes.
Methods
- Mouse embryonic liver tissue from wild-type, Tbx3+/−, and Tbx3−/− embryos was analyzed, mainly at E12.5–E13.5.
- Hepatoblasts were prospectively isolated by flow cytometry as c-Met+ c-Kit− CD45− Ter119− cells and analyzed by clonal single-cell culture, immunofluorescence, RT-PCR, and qPCR.
- Loss- and gain-of-function experiments used Tbx3−/− mice, Tbx3-shRNA, p19ARF-siRNA, and p19ARF overexpression in cultured hepatoblasts.
Limitations
- The paper states that the transcriptional hierarchy involved in hepatoblast lineage determination should be elucidated in future analyses.
- The paper notes that phenotypic alterations in Tbx3−/− embryonic liver may also involve subsequent misinteractions of hepatoblasts with other hepatic components, although it argues the defects arise directly from hepatoblasts.
- Evident from the text: the causal evidence relies heavily on mouse embryonic liver and cultured hepatoblast assays; in vivo rescue of the Tbx3−/− phenotype is not shown, and implications for regeneration or carcinogenesis are discussed but not directly tested.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
8 of 14 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured
- Premisecitation§ INTRODUCTION
Isolating c-Met+ c-Kit- CD45- Ter119- cells achieves a much higher enrichment of hepatoblasts.
“Isolating c-Met + c-Kit - CD45 -Ter119 -(also known as Met, Kit, Ptprc and Ly76, respectively -Mouse Genome Informatics) cells achieved a much higher enrichment of hepatoblasts, and thus this method could facilitate the identification of a discrete set of transcription factors that are activated in this specific cell population.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Suzuki et al., 2000 source
- cites Suzuki et al., 2002 source
The Results section, “Flow cytometric fractionation of fetal mouse liver cells” (page unavailable), reports 560-fold enrichment of hepatic colony-forming cells. But that enrichment required sorting for CD49f+/low as well as the four markers named in the claim; the paper does not establish the same enrichment for the four-marker selection alone. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Findingown data§ RESEARCH REPORT
Tbx3-deficient epithelial cells in the embryonic liver are composed of a few primitive hepatic cells and differentiating hepatocytes marked by Hnf4α and Alb, as well as a relatively large number of CK7+ cholangiocytes.
“Those Tbx3deficient epithelial cells were composed of a few primitive hepatic cells and differentiating hepatocytes that were marked by the expression of Hnf4α and Alb, as well as a relatively large number of CK7 + cholangiocytes (Fig. 2N-Q).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS AND DISCUSSION
In E13.5 liver, Tbx3 is detected only in a portion of Hnf4α+ cells, including primitive hepatic cells and differentiating hepatocytes.
“by E13.5 Tbx3 was detected only in a portion of Hnf4α + cells, including primitive hepatic cells and differentiating hepatocytes (Fig. 1E-I).”
Quote in the paperNot a substantial claim - Findingown data§ RESEARCH REPORT
Overexpression of p19ARF in cultures of wild-type c-Met+ c-Kit- CD45- Ter119- cells results in a significant reduction in the number of proliferating cells.
“Consistent with the data from the Tbx3 -/-liver, the overexpression of p19 ARF resulted in a significant reduction in the number of proliferating cells (Fig. 4K).”
Quote in the paperSubstantial claim - Findingown data§ RESEARCH REPORT
The percentages of PCNA+ cells in Hnf4α+ cells were 68.8% in wild-type and 27.3% in Tbx3-/- embryonic livers.
“The percentages of PCNA + cells in Hnf4α + cells were 68.8% and 27.3% in the livers of wildtype and Tbx3 -/-embryos, respectively.”
Quote in the paperSubstantial claim
- Findingown data§ RESEARCH REPORT
The defect in proliferation of Tbx3-shRNA-expressing hepatoblast progeny in culture is partially rescued by introducing p19ARF-siRNA.
“In addition, the defect in proliferation of Tbx3-shRNA-expressing hepatoblast progeny in culture was partially rescued by introducing p19 ARF -small interfering RNA (p19 ARF -siRNA) (see Fig. S4D,E in the supplementary material).”
Quote in the paperSubstantial claim - Findingown data§ RESEARCH REPORT
In the liver of Tbx3-/- embryos, the percentage of c-Met+ cells within the c-Kit- CD45- Ter119- hepatic epithelial cell population is less than half of that from wild-type embryos.
“In the liver of the Tbx3 -/-embryo, the percentage of c-Met + cells within the c-Kit - CD45 -Ter119 -hepatic epithelial cell population was less than half of that from wild-type embryos, suggesting a defect in in vivo hepatoblast proliferation (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data§ RESEARCH REPORT
In clonal colonies formed by c-Met+ c-Kit- CD45- Ter119- cells, p19ARF expression level is much higher in cultures of Tbx3-/- liver cells than in wild-type at day 5.
“Cells in colonies formed by c-Met + c-Kit -CD45 -Ter119 -cells isolated from either wild-type or Tbx3 -/-liver expressed p19 ARF at day 5 of culture, but its expression level was much higher in the cultures of Tbx3 -/-liver cells (Fig. 4B-G).”
Quote in the paperSubstantial claim - Findingown data§ RESEARCH REPORT
The E12.5 Tbx3-/- embryonic liver is much smaller than that of Tbx3+/+ wild-type or Tbx3+/- heterozygous embryos.
“The E12.5 Tbx3 -/-embryonic liver was much smaller than those from Tbx3 +/+ wild-type or Tbx3 +/-heterozygous embryos (Fig. 2A-C, and data not shown).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS AND DISCUSSION
Among 17 mouse T-box genes, Eomes, Tbx3, Tbx6, Tbx10, Tbx12, Tbx15 and Tbx20 are expressed in the E13.5 mouse liver.
“As an initial approach, we examined the hepatic expression of multiple T-box genes in E13.5 mouse embryos and identified the specific expression of Eomes, Tbx3, Tbx6, Tbx10, Tbx12, Tbx15 and Tbx20 (Fig. 1A).”
Quote in the paperSubstantial claim - Findingown data§ RESEARCH REPORT
In later stages of liver development, Tbx3 expression decreases and becomes faint in Hnf4α+ cells during the advancement of hepatocyte differentiation.
“In the later stages of liver development, however, Tbx3 expression decreased and became faint in Hnf4α + cells during the advancement of hepatocyte differentiation (see Fig. S1M-V in the supplementary material).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS AND DISCUSSION
Tbx3 expression is much higher in the c-Met+ c-Kit- CD45- Ter119- hepatoblast population than in c-Met- cells.
“Further fractionation of c-Kit -CD45 -Ter119 -cells into c-Met + or c-Met -cells revealed that Tbx3 expression was much higher in the c-Met + c-Kit -CD45 - Ter119 -hepatoblast population (Fig. 1B,D).”
Quote in the paperSubstantial claim - Findingown data§ Atsushi Suzuki
Tbx3 is specifically expressed in multipotent hepatic progenitor cells (hepatoblasts) isolated from the developing mouse liver.
“Here we show that Tbx3, the T-box gene that is mutated in human ulnar-mammary syndrome, is specifically expressed in multipotent hepatic progenitor cells, 'hepatoblasts', isolated from the developing mouse liver.”
- Also stated in: § RESULTS AND DISCUSSION · plain
“Significantly, only Tbx3, the T-box gene that is mutated in human ulnar-mammary syndrome (Bamshad et al., 1997), was expressed in c-Kit -CD45 - Ter119 -hepatic epithelial cells, and Tbx3 expression was restricted to this cell population (Fig. 1C).”
Quote in the paperSubstantial claim - Also stated in: § RESULTS AND DISCUSSION · plain
- Findingown data§ RESEARCH REPORT
In Tbx3-/- embryonic liver, expression of genes encoding cholangiocyte markers (CK19, CK7) and transcription factors that control cholangiocyte differentiation (Hnf1β, Hnf6) are upregulated.
“although the expression of genes encoding cholangiocyte markers [CK19 (Krt19) and CK7] and transcription factors that control cholangiocyte differentiation (Hnf1β and Hnf6) (Clotman et al., 2002;Coffinier et al., 2002) were all upregulated (Fig. 2R).”
Quote in the paperSubstantial claim - Findingown data§ RESEARCH REPORT
Restoring Tbx3 expression by transgenes significantly decreases p19ARF expression in Tbx3-/- colony cells.
“When Tbx3 expression was restored by transgenes, a significant decrease of p19 ARF expression was exhibited in Tbx3 -/- colony cells (Fig. 4H-J).”
Quote in the paperSubstantial claim - Interpretationown data§ RESEARCH REPORT
The growth arrest induced by active p19ARF in the absence or suppression of Tbx3 function is sufficient to promote cholangiocyte differentiation from hepatoblasts.
“Thus, the growth arrest induced by active p19 ARF in the absence or suppression of Tbx3 function is sufficient to promote cholangiocyte differentiation from hepatoblasts.”
Quote in the paperSubstantial claim - Premisecitation§ RESEARCH REPORT
Tbx3 controls a hyperproliferative feature of hepatic carcinoma cells.
“Analogous to the results shown above, evidence from loss-of-function experiments demonstrated that Tbx3, which was also highly expressed in hepatic carcinoma cells, controlled a hyperproliferative feature of these cells (Renard et al., 2007).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Renard et al., 2007 source
- May combine two claims. 16
- Classified as probably not a substantial claim. 4
May combine two claims.
Premisecitation§ RESEARCH REPORTTbx3 is a transcriptional repressor for p19ARF and p14ARF.
“Tbx3 is known as a transcriptional repressor for p19 ARF (Cdkn2a -Mouse Genome Informatics) and p14 ARF (the human ortholog of p19 ARF )”
Quote in the paperSubstantial claim3 of 3 sources checked- cites Honda and Yasuda, 1999 source
The Introduction (page unavailable) discusses p19ARF binding to Mdm2, and Materials and methods (page unavailable) identifies the p19ARF used as mouse-derived. Searches for Tbx3-mediated transcriptional repression and p14ARF as the human ortholog found no passage addressing either point. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites Brummelkamp et al., 2002 source
- cites Lingbeek et al., 2002 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ INTRODUCTIONc-Met+ cells display self-renewing cell divisions and differentiation into both hepatocytes and cholangiocytes in response to Hgf stimulus.
“In particular, cells marked by the hepatocyte growth factor (Hgf) receptor c-Met displayed distinctive activities in response to Hgf stimulus, including self-renewing cell divisions and differentiation into both hepatocytes and cholangiocytes (Suzuki et al., 2002;Suzuki et al., 2003a).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites Suzuki et al., 2002 source
The Results (Flow cytometric fractionation; Clonal expansion and self-renewal capability) identify self-renewing, multilineage H-CFU-C within the c-Met+ cell subpopulation and state that HGF is required for their proliferation. The Discussion (Self-renewal of H-CFU-C in vitro and in vivo) reports divisions yielding both hepatocytes and cholangiocytes, but the cited passages do not establish that HGF stimulus drives differentiation into both lineages. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites Suzuki et al., 2003a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
Premisecitation§ RESEARCH REPORTp19ARF and p14ARF are tumor suppressor genes that stabilize p53 via inactivation of Mdm2 in response to oncogenic stresses.
“the tumor suppressor genes that stabilize p53 (Trp53) via inactivation of Mdm2 in response to a variety of oncogenic stresses (Honda and Yasuda, 1999;Brummelkamp et al., 2002;Lingbeek et al., 2002;Kim and Sharpless, 2006).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites Honda and Yasuda, 1999 source
The Abstract and the ‘Effect of p19 ARF on Mdm2 activity’ section report that p19ARF inhibits Mdm2 activity, promoting p53 stabilization. The paper does not address p14ARF, and it does not establish this mechanism as a response to a variety of oncogenic stresses; its Introduction discusses genotoxic stress separately. No page numbers are available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites Brummelkamp et al., 2002 source
- cites Lingbeek et al., 2002 source
The opening background passage (page unavailable) identifies mouse p19ARF and human p14ARF as counterparts and says p19ARF is induced by oncogenic signaling and leads via MDM2 to stable, active p53. It does not explicitly say that ARF inactivates MDM2, so that specific mechanism is not established by our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
Findingown data§ RESEARCH REPORTIn Tbx3-/- embryonic liver, the number of BrdU-incorporating or PCNA+ proliferating cells decreases substantially without any increase in apoptotic cells.
“Indeed, when compared with cells from the wild-type liver, the number of BrdU-incorporating or PCNA + proliferating cells decreased substantially in the absence of Tbx3 (Fig. 2F-I and see Fig. S2 in the supplementary material) without any increase in the number of apoptotic cells (see Fig. S3 in the supplementary material).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESEARCH REPORTIn Tbx3-/- embryonic liver, the number of E-cadherin+ epithelial cells is significantly reduced, whereas the number of N-cadherin+ mesenchymal cells is not affected.
“Additionally, in the Tbx3 -/-embryonic liver, the number of E-cadherin + epithelial cells was also significantly reduced, whereas the number of N-cadherin + (Ecadherin -) mesenchymal cells was not affected (Fig. 2J-M).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESEARCH REPORTAt day 18 of culture, wild-type colonies contain approximately 25% Alb+ hepatocytes and 60% CK7+ cholangiocytes; Tbx3-/- colonies contain 95% CK7+ cholangiocytes and only approximately 2% Alb+ hepatocytes.
“At day 18 of culture, differentiating Alb + hepatocytes (~25%) and CK7 + cholangiocytes (~60%) appeared in colonies formed by wild-type cells (Fig. 3E,F,H).In the case of Tbx3 -/-colonies, however, 95% of the cells became CK7 + cholangiocytes, and only a few Alb + hepatocytes (~2%) emerged (Fig. 3G,H).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESEARCH REPORTSuppression of endogenous Tbx3 by Tbx3-shRNA in cultured hepatoblast progeny inhibits hepatoblast proliferation, represses expression of genes activated during hepatocyte differentiation, and enhances cholangiocyte marker expression.
“Consistent with the results from the Tbx3 -/-liver study, efficient suppression of endogenous Tbx3 expression inhibited hepatoblast proliferation, repressed the expression of several genes activated during hepatocyte differentiation, and enhanced cholangiocyte marker expression (see Fig. S4C,E-H in the supplementary material).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESEARCH REPORTp19ARF overexpression upregulates expression of CK19 and CK7 and increases the number of CK7+ cholangiocytes.
“Surprisingly, p19 ARF overexpression was also effective in upregulating the expression of CK19 and CK7 and increased the number of CK7 + cholangiocytes (Fig. 4L-S).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESEARCH REPORTIn Tbx3-/- embryonic liver, expression levels of genes encoding hepatocyte differentiation markers (Alb, αAT), primitive hepatic cell markers (Afp, c-Met), and transcription factors involved in early hepatocyte differentiation (C/EBPα, Hnf1α, Hnf4α) are all markedly diminished.
“Quantitative PCR (qPCR) analysis also demonstrated that the expression levels of genes encoding hepatocyte differentiation markers [Alb and α-1antitrypsin (αAT; Serpina1 -Mouse Genome Informatics)], primitive hepatic cell markers [α-fetoprotein (Afp) and c-Met], and transcription factors involved in the early stage of hepatocyte differentiation (C/EBPα, Hnf1α and Hnf4α) were all markedly dim”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESEARCH REPORTColony formation by c-Met+ c-Kit- CD45- Ter119- cells from Tbx3-/- liver is significantly impaired, and only small colonies form, despite normal cell attachment.
“As a result of deleting the Tbx3 gene, colony formation by c-Met + c-Kit -CD45 -Ter119 -cells was significantly impaired, and only small colonies formed, despite cell attachment onto the bottom of wells being normal (Fig. 3C,D).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ RESEARCH REPORTIn the developing liver, Tbx3 acts not only as an activator for proliferation, but also as a regulator for hepatobiliary lineage segregation.
“Therefore, in the developing liver, Tbx3 acts not only as an activator for proliferation, but also as a regulator for hepatobiliary lineage segregation.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ RESEARCH REPORTTbx3 plays an essential role in hepatogenesis by controlling the proliferation and the cell-lineage decision of hepatoblasts.
“Taken together, we conclude that Tbx3 plays an essential role in hepatogenesis by controlling the proliferation and the cell-lineage decision of hepatoblasts.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ Atsushi SuzukiTbx3 plays a crucial role in controlling hepatoblast proliferation and cell-fate determination by suppressing p19ARF expression and thereby promoting liver organogenesis.
“Thus, Tbx3 plays a crucial role in controlling hepatoblast proliferation and cell-fate determination by suppressing p19 ARF expression and thereby promoting liver organogenesis.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Atsushi SuzukiTbx3 is the T-box gene that is mutated in human ulnar-mammary syndrome.
“Here we show that Tbx3, the T-box gene that is mutated in human ulnar-mammary syndrome, is specifically expressed in multipotent hepatic progenitor cells, 'hepatoblasts', isolated from the developing mouse liver.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bamshad et al., 1997 source
May combine two claims.
Premisereasoning§ RESEARCH REPORTIn cancer cells, Tbx3 negatively regulates p19ARF expression to induce escape from cellular senescence and to activate mitosis.
“This evidence suggests that in cancer cells, Tbx3 negatively regulates p19 ARF expression to induce escape from cellular senescence and to activate mitosis.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ RESEARCH REPORTThe phenotypic alterations in the Tbx3-/- embryonic liver arose as a direct consequence of the developmental defects of hepatoblasts, although subsequent misinteractions of hepatoblasts with other hepatic components might also be relevant.
“Therefore, the phenotypic alterations in the Tbx3 -/- embryonic liver arose as a direct consequence of the developmental defects of hepatoblasts, although the subsequent misinteractions of hepatoblasts with other hepatic components might also be relevant to that phenotype.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ RESEARCH REPORTTbx3 might act as a central regulator for maintaining cells in an undifferentiated state and for activating their proliferation to create the basis of liver organogenesis, until its expression ceases or is superseded by subsequent activation of other transcription factors required for differentiation.
“Therefore, although a transcriptional hierarchy involved in the lineage determination of hepatoblasts should be elucidated in future analyses, Tbx3 might act as a central regulator for maintaining cells in an undifferentiated state and for activating their proliferation to create the basis of liver organogenesis, until such a time that its expression ceases or is superseded by the subsequent”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisecitation§ RESEARCH REPORTIn the intestine, the molecular mechanisms governing homeostatic self-renewal of stem cells and aberrant proliferation of colorectal cancer cells are similar.
“In the intestine, the molecular mechanisms governing the homeostatic selfrenewal of stem cells and the aberrant proliferation of colorectal cancer cells are similar (Radtke and Clevers, 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Radtke and Clevers, 2005 source
May combine two claims.
Premisecitation§ RESEARCH REPORTThe phenotypic features of Tbx3-/- embryos, including diminished liver size, have also been observed in another Tbx3 mutant mouse line, but such liver defects were only discussed as an effect of deficiencies in yolk sac or hematovascular development.
“The phenotypic features of Tbx3 -/-embryos, including a diminished liver size, have also been observed in another Tbx3 mutant mouse line, but such liver defects were only discussed as an effect of deficiencies in the yolk sac or in hematovascular development (Davenport et al., 2003).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Davenport et al., 2003 source
The paper relies on this without support.
No previous evidence implicated a role for Tbx3 in hepatogenesis.
“In our study, although there was no previous evidence to implicate a role for Tbx3 in hepatogenesis, searching for T-box genes that are expressed specifically in hepatoblasts led to the identification of Tbx3 as an essential regulator for the proliferation and differentation of hepatoblasts.”
The paper relies on this without support.
The role of T-box family transcription factors in liver development is unknown.
“Although the T-box family of transcription factors function in many different tissues, their role in liver development is unknown.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Tbx3 maintains expression of hepatocyte-lineage genes and represses cholangiocyte fate.
“Tbx3 also maintains expression of hepatocyte-lineage genes, such as Cebpα and Hnf4α, and represses the cholangiocyte fate (23, 24).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [24]
Tbx3 is a gene required for embryonic liver development.
“The transcriptional repressor Tbx3, a gene required for embryonic liver development (Khan et al. 2020;Ludtke et al. 2009;Suzuki et al. 2008)”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Suzuki et al. 2008
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“Analogous to the results shown above, evidence from loss-of-function experiments demonstrated that Tbx3, which was also highly expressed in hepatic carcinoma cells, controlled a hyperproliferative feature of these cells (Renard et al., 2007).”
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Glucagon-like peptide 1 (1–37) converts intestinal epithelial cells into insulin-producing cells
Suzuki, A., Nakauchi, H., & Taniguchi, H. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0936260100 · Cited by 140 · see citing works
Self-citationTbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling
Ribeiro, I., Kawakami, Y., Büscher, D., Raya, Á., Rodríguez-León, J., Morita, M., Rodríguez-Esteban, C., & Belmonte, J. C. I. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000398 · Cited by 108 · see citing works
Yamasaki, H., Sada, A., Iwata, T., Niwa, T., Tomizawa, M., Xanthopoulos, K. G., Koike, T., & Shiojiri, N. (2006) · Development · doi:10.1242/dev.02591 · Cited by 99 · see citing works
Tomizawa, M., Garfield, S. H., Factor, V. M., & Xanthopoulos, K. G. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.8999 · Cited by 44 · see citing works
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Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis
Sia, D., Villanueva, A., Friedman, S., & Llovet, J. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.11.048 · Cited by 1,051 · see citing works
Organogenesis and development of the liver
Si-Tayeb, K., Lemaigre, F. P., & Duncan, S. A. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.01.011 · Cited by 800 · see citing works
Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver
Wang, B., Zhao, L., Fish, M., Logan, C. Y., & Nusse, R. (2015) · Nature · doi:10.1038/nature14863 · Cited by 674 · see citing works
“The stem cell marker Tbx3 is expressed widely in early liver hepatoblasts and is important for hepatoblast proliferation and initiation of hepatocyte differentiation[19, 37].”
BackgroundGeneration and Regeneration of Cells of the Liver and Pancreas
Zaret, K., & Grompe, M. (2008) · Science · doi:10.1126/science.1161431 · Cited by 601 · see citing works
Necroptosis microenvironment directs lineage commitment in liver cancer
Seehawer, M., Heinzmann, F., D’Artista, L., Harbig, J., Roux, P.-F., Hoenicke, L., Dang, H., Klotz, S., Robinson, L., Doré, G., et al. (2018) · Nature · doi:10.1038/s41586-018-0519-y · Cited by 406 · see citing works
Directed differentiation of cholangiocytes from human pluripotent stem cells
Ogawa, M., Ogawa, S., Bear, C. E., Ahmadi, S., Chin, S., Li, B., Grompe, M., Keller, G. M., Kamath, B. M., & Ghanekar, A. (2015) · Nature Biotechnology · doi:10.1038/nbt.3294 · Cited by 318 · see citing works
Liver regeneration and inflammation: from fundamental science to clinical applications
Campana, L., Esser, H., Huch, M., & Forbes, S. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00373-7 · Cited by 307 · see citing works
The T-box gene family: emerging roles in development, stem cells and cancer
Papaioannou, V. E. (2014) · Development · doi:10.1242/dev.104471 · Cited by 293 · see citing works
Human Pluripotent Stem Cell-Derived Organoids as Models of Liver Disease
Ramli, M. N. B., Lim, Y. S., Koe, C. T., Demircioglu, D., Tng, W., Gonzales, K. A. U., Tan, C. P., Szczerbinska, I., Liang, H., Soe, E. L., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.06.010 · Cited by 278 · see citing works
Lemaigre, F. P. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.03.035 · Cited by 263 · see citing works
Generation of hepatobiliary organoids from human induced pluripotent stem cells
Wu, F., Wu, D., Ren, Y., Huang, Y., Feng, B., Zhao, N. J., Zhang, T., Chen, X., Chen, S., & Xu, A. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2018.12.028 · Cited by 264 · see citing works
Human hepatic organoids for the analysis of human genetic diseases
Guan, Y., Xu, D., Garfin, P. M., Ehmer, U., Hurwitz, M., Enns, G., Michie, S., Wu, M., Zheng, M., Nishimura, T., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.94954 · Cited by 243 · see citing works
From Progenitors to Differentiated Cells in the Vertebrate Retina
Agathocleous, M., & Harris, W. A. (2009) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.042308.113259 · Cited by 240 · see citing works
“2008) and liver (Suzuki et al. 2008).”
A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells
Ang, L. T., Tan, A. K. Y., Autio, M. I., Goh, S. H., Choo, S. H., Lee, K. L., Tan, J., Pan, B., Lee, J. J. H., Lum, J. J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.087 · Cited by 220 · see citing works
HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells
DeLaForest, A., Nagaoka, M., Si-Tayeb, K., Noto, F. K., Konopka, G., Battle, M. A., & Duncan, S. A. (2011) · Development · doi:10.1242/dev.062547 · Cited by 219 · see citing works
“As a comparative standard, we chose to relate signal levels to those measured for TBX3 because TBX3 has been shown to be required for mouse liver development (Suzuki et al., 2008; Ludtke et al., 2009).”
BackgroundBiliary differentiation and bile duct morphogenesis in development and disease
Raynaud, P., Carpentier, R., Antoniou, A., & Lemaigre, F. P. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.07.020 · Cited by 154 · see citing works
The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis
Wagner, K., & Wagner, N. (2022) · Cells · doi:10.3390/cells11121966 · Cited by 156 · see citing works
“p14ARF/p19ARF is detectable in developing hepatoblasts [156], which agrees with our recent report.”
BackgroundResultInfluentialLiver stem/progenitor cells: their characteristics and regulatory mechanisms
Tanaka, M., Itoh, T., Tanimizu, N., & Miyajima, A. (2011) · The Journal of Biochemistry · doi:10.1093/jb/mvr001 · Cited by 135 · see citing works
Understanding the marvels behind liver regeneration
Rmilah, A. A. A., Zhou, W., Nelson, E., Li, L., Amiot, B. P., & Nyberg, S. L. (2019) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.340 · Cited by 133 · see citing works
Stem cells in gastroenterology and hepatology
Quante, M., & Wang, T. C. (2009) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2009.195 · Cited by 130 · see citing works
“A transcription factor, TBX3, helps expand the hepatoblast population by suppressing CDKN2A”
Lüdtke, T. H. ‐., Christoffels, V. M., Petry, M., & Kispert, A. (2009) · Hepatology · doi:10.1002/hep.22700 · Cited by 117 · see citing works
Oncogenic driver genes and tumor microenvironment determine the type of liver cancer
Wang, G., Wang, Q., Liang, N. N., Xue, H., Yang, T., Chen, X., Qiu, Z., Zeng, C., Sun, T., Yuan, W., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2509-x · Cited by 109 · see citing works
Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control
Brosch, M., Kattler, K., Herrmann, A., von Schönfels, W., Nordström, K., Seehofer, D., Damm, G., Becker, T., Zeissig, S., Nehring, S., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06611-5 · Cited by 98 · see citing works
The roles and regulation of TBX3 in development and disease
Khan, S. F., Damerell, V., Omar, R., Du Toit, M., Khan, M., Maranyane, H. M., Mlaza, M., Bleloch, J., Bellis, C., Sahm, B. D. B., et al. (2020) · Gene · doi:10.1016/j.gene.2019.144223 · Cited by 99 · see citing works
Molecular mechanisms of bile duct development
Zong, Y., & Stanger, B. Z. (2010) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2010.06.020 · Cited by 95 · see citing works
“Expression of Foxa1 is upregulated in HNF6 null livers, probably due to the upregulation of TGFβ signaling (Plumb-Rudewiez et al., 2004).”
BackgroundInfluentialKim, H., Im, I., Jeon, J. S., Kang, E.-H., Lee, H., Jo, S., Kim, J., Woo, D., Choi, Y. J., Kim, H. J., et al. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121575 · Cited by 82 · see citing works
Tbx2 Controls Lung Growth by Direct Repression of the Cell Cycle Inhibitor Genes Cdkn1a and Cdkn1b
Lüdtke, T. H., Farin, H. F., Rudat, C., Schuster-Gossler, K., Petry, M., Barnett, P., Christoffels, V. M., & Kispert, A. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003189 · Cited by 79 · see citing works
Nagao, M., Campbell, K., Burns, K. A., Kuan, C.-Y., Trumpp, A., & Nakafuku, M. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200807130 · Cited by 74 · see citing works
“Recent studies have also begun to reveal their vital roles in normal development ( Suzuki et al., 2008 ; for review see Murphy et al., 2005 ).”
ARF tumor suppression in the nucleolus
Maggi, L. B., Winkeler, C. L., Miceli, A. P., Apicelli, A. J., Brady, S. N., Kuchenreuther, M., & Weber, J. D. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.01.016 · Cited by 69 · see citing works
Molecular mechanisms of liver and bile duct development
Zong, Y., & Stanger, B. Z. (2012) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.47 · Cited by 65 · see citing works
Klochendler, A., Weinberg-Corem, N., Moran, M., Swisa, A., Pochet, N. L. M. M., Savova, V., Vikeså, J., de Peer, Y. V., Brandeis, M., Regev, A., et al. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.08.009 · Cited by 62 · see citing works
Regulation of hepatocyte identity and quiescence
Berasain, C., & Avila, M. A. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1970-7 · Cited by 62 · see citing works
“The transcriptional repressor TBX3 appears to be essential for hepatocyte differentiation, as its elimination promotes biliary differentiation at the expense of hepatocyte specification [49].”
BackgroundHepatic stem/progenitor cells and stem-cell transplantation for the treatment of liver disease
Kakinuma, S., Nakauchi, H., & Watanabe, M. (2009) · Journal of Gastroenterology · doi:10.1007/s00535-008-2297-z · Cited by 60 · see citing works
“On the other hand, Tbx3, one of the T-box genes, controls the fate of fetal hepatic stem/ progenitor cells by suppressing p19 expression.(19) As a result, Tbx3-defi cient hepatic stem/progenitor cells exhibit cholangiocytic lineage segregation.”
BackgroundDiverse functional networks of <i>Tbx3</i> in development and disease
Washkowitz, A. J., Gavrilov, S., Begum, S., & Papaioannou, V. E. (2012) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1162 · Cited by 58 · see citing works
Shiraki, N., Yamazoe, T., Zeng, Q., Ohgomori, K., Mochitate, K., Kume, K., & Kume, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024228 · Cited by 56 · see citing works
“collagen types I and IV facilitated the hepatic differentiation of a subpopulation of hepatic stem cells isolated by flow cytometry [39].”
BackgroundDeLaForest, A., Furio, F. D., Jing, R., Ludwig-Kubinski, A., Twaroski, K., Urick, A., Pulakanti, K., Rao, S., & Duncan, S. A. (2018) · Genes · doi:10.3390/genes10010021 · Cited by 56 · see citing works
Functional identity of hypothalamic melanocortin neurons depends on Tbx3
Quarta, C., Fisette, A., Xu, Y., Colldén, G., Legutko, B., Tseng, Y.-T., Reim, A., Wierer, M., De Rosa, M. C., Klaus, V., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-018-0028-1 · Cited by 54 · see citing works
Mu, T., Xu, L., Zhong, Y., Liu, X., Zhao, Z., Huang, C., Lan, X., Lufei, C., Zhou, Y., Su, Y., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-01364-8 · Cited by 52 · see citing works
Seth, A., Ye, J., Yu, N., Guez, F., Bedford, D. C., Neale, G. A., Cordi, S., Brindle, P. K., Lemaigre, F. P., Kaestner, K. H., et al. (2014) · Development · doi:10.1242/dev.099481 · Cited by 50 · see citing works
“…that in this network Tbx3 acts upstream of Prox1 because, similar to our report in Prox1-null mice (Sosa-Pineda et al., 2000), the hepatic precursors of Tbx3-null embryos had reduced proliferation, and these cells did not delaminate from the gut endoderm (Lüdtke et al., 2009; Suzuki et al., 2008).”
BackgroundResultBoyd, S. C., Mijatov, B., Pupo, G. M., Tran, S. L., Gowrishankar, K., Shaw, H. M., Goding, C. R., Scolyer, R. A., Mann, G. J., Kefford, R. F., et al. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2012.421 · Cited by 53 · see citing works
“Tbx3, a member of the T-box family of developmental regulators (Bamshad et al., 1997; Lee et al., 2007; Rowley et al., 2004; Suzuki et al., 2008) has been strongly implicated in cancer (Hoek et al.”
BackgroundGene regulatory networks in differentiation and direct reprogramming of hepatic cells
Gérard, C., Tys, J., & Lemaigre, F. P. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.12.003 · Cited by 46 · see citing works
Zirzow, S., Lüdtke, T. H., Brons, J. F., Petry, M., Christoffels, V. M., & Kispert, A. (2009) · Developmental Biology · doi:10.1016/j.ydbio.2009.09.020 · Cited by 46 · see citing works
“5 most likely due to a combination of cardiac, vascular and hepatic defects (Davenport et al., 2003; Ludtke et al., 2009; Suzuki et al., 2008).”
BackgroundOncofetal Gene SALL4 in Aggressive Hepatocellular Carcinoma
Hopkins, L., Rowe, I. A. C., & Houlihan, D. D. (2013) · New England Journal of Medicine · doi:10.1056/nejmc1308785 · Cited by 45 · see citing works
The T-Box transcription factor 3 in development and cancer
Willmer, T., Cooper, A., Peres, J., Omar, R., & Prince, S. (2017) · BioScience Trends · doi:10.5582/bst.2017.01043 · Cited by 44 · see citing works
“In line with this, depletion of Tbx3 inhibits proliferation of hepatic progenitor cells with a corresponding increase in p19ARF mRNA levels and Tbx3 mouse livers exhibit increased p19ARF and p21 levels although p53 levels remained unaffected (53).”
BackgroundThe special stemness functions of Tbx3 in stem cells and cancer development
Dong, L., Lyu, X., Faleti, O. D., & He, M.-L. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.09.010 · Cited by 41 · see citing works
Takashima, Y., Terada, M., Udono, M., Miura, S., Yamamoto, J., & Suzuki, A. (2016) · Hepatology · doi:10.1002/hep.28548 · Cited by 40 · see citing works
Self-citationMolecular Mechanisms of Biliary Development
Lemaigre, F. P. (2010) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385233-5.00004-0 · Cited by 39 · see citing works
Willmer, T., Hare, S., Peres, J., & Prince, S. (2016) · Cell Division · doi:10.1186/s13008-016-0019-0 · Cited by 38 · see citing works
“Indeed, there is evidence to suggest that TBX3 may also repress p21 transcriptionally [28] and we and others have shown an inverse correlation between the ability of TBX3 to promote proliferation of chondrosarcoma, mammary epithelial and hepatic progenitor cells and p21 levels [13, 29, 30].”
BackgroundWnt5a signaling mediates biliary differentiation of fetal hepatic stem/progenitor cells in mice
Kiyohashi, K., Kakinuma, S., Kamiya, A., et al. (2013) · Hepatology · doi:10.1002/hep.26293 · Cited by 36 · see citing works
Dong, L., Dong, Q., Chen, Y., Li, Y., Zhang, B., Zhou, F., Lyu, X., Chen, G. G., Lai, P., Kung, H.-F., et al. (2018) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-018-0025-6 · Cited by 36 · see citing works
Negishi, T., Nagai, Y., Asaoka, Y., Ohno, M., Namae, M., Mitani, H., Sasaki, T., Shimizu, N., Terai, S., Sakaida, I., et al. (2009) · Hepatology · doi:10.1002/hep.23387 · Cited by 36 · see citing works
“Red, green, and blue horizontal lines indicate the RALDH2 catalytic domain (289-503), nucleotide binding domain (20-154, 179-288), and tetramerization domain (155-178, 504-518), respectively.”
BackgroundRegulation of organogenesis and stem cell properties by T-box transcription factors
Takashima, Y., & Suzuki, A. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1305-5 · Cited by 33 · see citing works
Self-citationTissue-specific NETs alter genome organization and regulation even in a heterologous system
Heras, J. I. D. L., Zuleger, N., Batrakou, D. G., Czapiewski, R., Kerr, A. R. W., & Schirmer, E. C. (2017) · Nucleus · doi:10.1080/19491034.2016.1261230 · Cited by 35 · see citing works
“Again many of the most affected genes are notably important for liver function such as cytochrome B (CYBRD1), peptidylprolyl isomerase C (PPIC) and tryptophan 2,3-dioxygenase (TDO2) or liver differentiation such as the Tbox transcription factor TBX3.(33) The effects of NET29 were milder and no significant association…”
BackgroundZaret, K. S. (2016) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2015.12.015 · Cited by 34 · see citing works
Derivation of endodermal progenitors from pluripotent stem cells
Ikonomou, L., & Kotton, D. (2015) · Journal of Cellular Physiology · doi:10.1002/jcp.24771 · Cited by 29 · see citing works
“, 2000] or preferential cholangiocyte differentiation (Tbx3) [Suzuki et al., 2008].”
Epithelial Morphogenesis during Liver DevelopmentPreprint
Tanimizu, N., & Mitaka, T. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a027862 · Cited by 31 · see citing works
Okada, K., Kamiya, A., Ito, K., Yanagida, A., Ito, H., Kondou, H., Nishina, H., & Nakauchi, H. (2011) · Stem Cells and Development · doi:10.1089/scd.2011.0229 · Cited by 30 · see citing works
“Several transcription factors, such as Prox1, Tbx3, and Sall4, regulate proliferation and differentiation of hepatoblasts in liver development [11–13].”
The T-Box factor TBX3 is important in S-phase and is regulated by c-Myc and cyclin A-CDK2
Willmer, T., Peres, J., Mowla, S., Abrahams, A., & Prince, S. (2015) · Cell Cycle · doi:10.1080/15384101.2015.1080398 · Cited by 32 · see citing works
Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade
Jin, Y., Anbarchian, T., Wu, P., Sarkar, A., Fish, M., Peng, W. C., & Nusse, R. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2203849119 · Cited by 26 · see citing works
“Tbx3 also maintains expression of hepatocyte-lineage genes, such as Cebpα and Hnf4α, and represses the cholangiocyte fate (23, 24).”
BackgroundInterspecies Organogenesis for Human Transplantation
Crane, A. T., Aravalli, R. N., Asakura, A., Grande, A. W., Krishna, V. D., Carlson, D. F., Cheeran, M. C. ‐., Danczyk, G., Dutton, J. R., Hackett, P. B., et al. (2019) · Cell Transplantation · doi:10.1177/0963689719845351 · Cited by 26 · see citing works
Sarkar, A., Jin, Y., DeFelice, B. C., Logan, C. Y., Yang, Y., Anbarchian, T., Wu, P. V., Morri, M., Neff, N. F., Nguyen, H., et al. (2022) · eLife · doi:10.7554/elife.82311 · Cited by 23 · see citing works
“Previous studies have demonstrated that Tbx3 regulates division of hepatoblasts during embryonic liver development by repressing cell cycle inhibitors (Suzuki et al. 2008).”
BackgroundREVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY
Lynch, J. P., Metz, D. C., Schuppan, D., Junker, Y., & Barisani, D. (2009) · Cited by 24 · see citing works
Molecular regulation of mammalian hepatic architecture
Huppert, S. S., & Iwafuchi, M. (2018) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2018.12.003 · Cited by 23 · see citing works
“The implicated regulator of growth arrest is p19ARF due to its over-expression in the absence of Tbx3 and known role as a tumor suppressor (Suzuki et al., 2008).”
BackgroundLiu, Y., El‐Serag, H. B., Jiao, L., Lee, J., Moore, D. D., Franco, L. M., Tavakoli–Tabasi, S., Tsavachidis, S., Kuzniarek, J., Ramsey, D. J., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0084407 · Cited by 21 · see citing works
“TBX3 is a downstream target of the Wnt signaling pathway and a critical mediator of Wnt activities on cell proliferation and survival [28], with TBX3 overexpression well-documented in liver tumorigenesis [29].”
BackgroundBallim, R. D., Mendelsohn, C. L., Papaioannou, V. E., & Prince, S. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-09-0790 · Cited by 19 · see citing works
“ation in hepatoblasts through repression of p19ARF (Suzuki et al., 2008).”
BackgroundWigger, L., Casals-Casas, C., Baruchet, M., Trang, K., Pradervand, S., Naldi, A., & Desvergne, B. (2019) · bioRxiv · doi:10.1371/journal.pone.0220894 · Cited by 17 · see citing works
“TBX3 is a transcription factor particularly important for hepatoblast proliferation [32].”
BackgroundCell-Based Regeneration and Treatment of Liver Diseases
Hofmann, J. D., Hackl, V., Esser, H., Mészáros, A., Fodor, M., Öfner, D., Troppmair, J., Schneeberger, S., & Hautz, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910276 · Cited by 22 · see citing works
Qian, Y., Shang, Z., Gao, Y., Wu, H., & Kong, X. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.05.014 · Cited by 18 · see citing works
Zonation, Zonation, Zonation: The Real Estate of the Liver
Yasaka, T. M., Kim, C., Meadows, V., & Monga, S. P. (2025) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-042624-091820 · Cited by 21 · see citing works
Transcriptional Control of Hepatocyte Differentiation
Nagaoka, M., & Duncan, S. A. (2010) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385233-5.00003-9 · Cited by 17 · see citing works
Liver development: lessons from knockout mice and mutant fish
Nakamura, T., & Nishina, H. (2009) · Hepatology Research · doi:10.1111/j.1872-034x.2009.00522.x · Cited by 16 · see citing works
Application of mesenchymal stem cells in liver fibrosis and regeneration
Liu, Z., Ren, J., Qiu, C., Wang, Y., & Zhang, T. (2024) · Liver Research · doi:10.1016/j.livres.2024.11.004 · Cited by 16 · see citing works
TBX3, a downstream target of TGF-β1, inhibits mesangial cell apoptosis
Wensing, L. A., & Campos, A. H. (2014) · Experimental Cell Research · doi:10.1016/j.yexcr.2014.08.022 · Cited by 15 · see citing works
Oropez, D., & Horb, M. E. (2011) · genesis · doi:10.1002/dvg.20828 · Cited by 14 · see citing works
“…for their role in mesoderm and ectoderm development, previous studies have shown that Tbx3, which is thought to act redundantly with Tbx2, acts as a transcriptional repressor and plays a role in liver progenitor proliferation and cell-fate determination (Ludtke et al., 2009; Suzuki et al., 2008).”
Hepatocyte-Ductal Transdifferentiation Is Mediated by Reciprocal Repression of SOX9 and C/EBPα
O’Neill, K. E., Thowfeequ, S., Li, W., Eberhard, D., Dutton, J. R., Tosh, D., & Slack, J. M. W. (2014) · Cellular Reprogramming · doi:10.1089/cell.2014.0032 · Cited by 13 · see citing works
“In normal embryonic development, hepatocytes and biliary epithelial cells are derived from a bipotential precursor, the hepatoblast (Strick-Marchand and Weiss, 2002; Suzuki et al., 2008; Tanimizu and Miyajima, 2004).”
BackgroundPflugfelder, G. O. (2008) · Journal of Neurogenetics · doi:10.1080/01677060802471619 · Cited by 13 · see citing works
Calabrese, D., Roma, G., Bergling, S., Carbone, W., Mele, V., Nuciforo, S., Fofana, I., Campana, B., Szkolnicka, D., Hay, D. C., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0221762 · Cited by 12 · see citing works
A Simple Code for Installing Hepatocyte Function
Willenbring, H. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.07.009 · Cited by 12 · see citing works
“…of iHep cells observed by Sekiya et al. was also facilitated by p19Arf suppression. p19Arf is suppressed by Tbx3 in embryonic liver progenitors (Suzuki et al., 2008), and although Sekiya et al. found that Tbx3 overexpression was not essential for iHep cell generation, it is possible that their…”
BackgroundOgoke, O., Yousef, O., Ott, C., Kalinousky, A. J., Lin, W., Shamul, C., Ross, S., & Parashurama, N. (2021) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2021.621286 · Cited by 10 · see citing works
Expression of TBX3 in Hepatocellular Carcinoma and Its Clinical Implication
Li, Z., Wang, Y., Duan, S., Shi, Y., Li, S., Zhang, X., & Ren, J. (2018) · Medical Science Monitor · doi:10.12659/msm.909378 · Cited by 11 · see citing works
“In the liver, TBX3 can inhibit the priming sequence of p19ARF in a specific way, thereby inhibiting the expression of p19ARF protein [20].”
BackgroundLocalized hepatic lobular regeneration by central-vein–associated lineage-restricted progenitors
Tsai, J. M., Koh, P. W., Stefańska, A., Xing, L., Walmsley, G. G., Poux, N., Weissman, I. L., & Rinkevich, Y. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1621361114 · Cited by 10 · see citing works
“The latter is an attractive possibility (35, 36), as their loss in postnatal life correlates with our observed postnatal loss o regeneration.”
BackgroundPrimary liver tumors: origin and target therapy
Papoulas, M., & Theocharis, S. E. (2009) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728220903074588 · Cited by 10 · see citing works
“, revealed that Tbx3, the T-box gene that is mutated in human ulnar-mammary syndrome, controls the proliferation and cell-fate determination of hepatic stem cells by suppressing p19ARF expression [45].”
BackgroundDNA Methylation Changes in Tbx3 in a Mouse Model Exposed to Polybrominated Diphenyl Ethers
Shimbo, T., Dunnick, J. K., Brix, A. E., Mav, D., Shah, R., Roberts, J. D., & Wade, P. A. (2017) · International Journal of Toxicology · doi:10.1177/1091581817706676 · Cited by 9 · see citing works
“Tbx3 is reported to maintain the proliferative state of hepatoblasts by suppressing the tumor suppressor p19ARF, a key regulator of cell cycle progression in normal cells.(32) We therefore tested whether upregulation of Tbx3 in HCC specimens from DE-71-exposed animals was associated with alterations in p19 status.”
BackgroundInfluentialKoike, H., Zhang, R., Ueno, Y., et al. (2017) · Development · doi:10.1242/dev.143032 · Cited by 9 · see citing works
“…et al., 2001), bonemorphogenetic proteins (Rossi et al., 2001) and fibroblast growth factors (Serls et al., 2005), and by transcriptional networks that act intrinsically in the HPCs, such as Tbx3 (Suzuki et al., 2008), Smad2/3 (Weinstein et al., 2001) and beta-catenin (Micsenyi et al., 2004).”
BackgroundInfluentialSelf-citationBlake, M. L., & Steer, C. J. (2024) · Hepatic Medicine Evidence and Research · doi:10.2147/hmer.s440697 · Cited by 8 · see citing works
“127 OC-1 and OC-2, another set of transcription factors, are also possible targets secondary to the role they play in the production of ɑ2-macroglobulin and follistatin.”
BackgroundStages based molecular mechanisms for generating cholangiocytes from liver stem/progenitor cells
Liu, W. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i41.7032 · Cited by 8 · see citing works
Ishibashi, R., Maki, R., Kitano, S., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-22639-6 · Cited by 8 · see citing works
Embryonic Development of the Liver
Bort, R., & Zaret, K. S. (2009) · Wiley eBooks · doi:10.1002/9780470747919.ch2 · Cited by 8 · see citing works
Zaret, K. S. (2015) · Nature · doi:10.1038/nature15201 · Cited by 7 · see citing works
The Use of Cellular Technologies in Treatment of Liver Pathologies
Petrakova, O. S., Степановна, Ч. Е., Terskikh, V. V., Kalistratova, E. N., & Vasiliev, A. V. (2012) · Acta Naturae · doi:10.32607/20758251-2012-4-3-16-30 · Cited by 7 · see citing works
A miR-212-3p/SLC6A1 Regulatory Sub-Network for the Prognosis of Hepatocellular Carcinoma
Zhang, D., Wang, W.-E., Ma, Y., Shi, Y., Yin, J., Liu, J., Yang, X., Xin, R., Fu, D., & Zhang, W. (2021) · Cancer Management and Research · doi:10.2147/cmar.s308986 · Cited by 7 · see citing works
Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma
Nagel, S., & Meyer, C. (2021) · PLoS ONE · doi:10.1371/journal.pone.0259674 · Cited by 7 · see citing works
Generation of Hepatocyte-Like Cells from Human Pluripotent Stem Cells
Noto, F. K., & Duncan, S. A. (2013) · Springer eBooks · doi:10.1007/978-1-4614-7696-2_10 · Cited by 7 · see citing works
Larson, E. L., Joo, D. J., Nelson, E., Amiot, B. P., Aravalli, R. N., & Nyberg, S. L. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.09.018 · Cited by 6 · see citing works
“Many of the genes described in Table 1 affect cell types beyond hepatocytes: UbC, TBX3, Mab21l2, and OC1/2 affect the common cholangiocyte and hepatocyte precursor, hepatoblasts (Kropp and Gannon, 2016; Ryu et al., 2007, 2012; Saito et al., 2012; Suzuki et al., 2008).”
BackgroundInfluentialWang, S., Yang, L., Sun, X., Wu, D., Fu, B., Chen, Y., Deng, H., & Chen, X. (2016) · PROTEOMICS · doi:10.1002/pmic.201600121 · Cited by 6 · see citing works
Mastrogiovanni, G., Pacini, C., Kakava, S., Arnes‐Benito, R., Bradshaw, C. R., Davies, S. E., Saeb‐Parsy, K., Koo, B., & Huch, M. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.09.25.313205 · Cited by 6 · see citing works
Developmental Anatomy and Physiology of the Liver and Bile Ducts
McLin, V. A., & Yazigi, N. A. (2010) · Elsevier eBooks · doi:10.1016/b978-1-4377-0774-8.10067-3 · Cited by 5 · see citing works
Expression of Chrna9 is regulated by Tbx3 in undifferentiated pluripotent stem cells
Yazawa, T., Imamichi, Y., Kitano, T., Islam, M. S., Khan, M. R. I., Takahashi, S., Sekiguchi, T., Suzuki, N., Umezawa, A., & Uwada, J. (2023) · Scientific Reports · doi:10.1038/s41598-023-28814-7 · Cited by 5 · see citing works
Development and Anatomy of the Bile Duct
Enomoto, K., & Nishikawa, Y. (2017) · Springer eBooks · doi:10.1007/978-981-10-3500-5_1 · Cited by 4 · see citing works
Molecular Mechanisms of Liver Development: Lessons From Animal Models
Miyamura, N., & Nishina, H. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812301-0.00001-3 · Cited by 6 · see citing works
- Authors
- Suzuki, A., Sekiya, S., Büscher, D., Izpisúa Belmonte, J. C., & Taniguchi, H.
- Affiliations
- Kyushu University (JP)
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
- RIKEN (JP)
- Corresponding author
- Suzuki, Atsushi
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2008-05-01
- Volume
- 135
- Issue
- 9
- Pages
- 1589-1595
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2144111415
- Semantic Scholar
- 72f61068eced0846efe8d93620bde4d9e5525bf0
- Cited by
- 136
- References
- 26
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 2 · 2023: 2 · 2022: 7 · 2021: 10 · 2020: 10 · 2019: 8 · 2018: 10 · 2017: 9 · 2016: 7 · 2015: 5 · 2014: 6 · 2013: 11 · 2012: 6
- FWCI
- 7.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Consorzio Interuniversitario Biotecnologie
- Ministry of Education, Culture, Sports, Science and Technology
- Ministerio de Economía y Competitividad
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- TBX3, hepatic progenitor cells, hepatoblasts, liver development, p19ARF, CDKN2A, cholangiocyte differentiation, cell fate determination, ulnar-mammary syndrome, liver organogenesis, tumor suppressor
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Liver, Cyclin-Dependent Kinase Inhibitor p16, T-Box Domain Proteins, Multipotent Stem Cells, Cell Proliferation, Mice
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