Journal of Hepatology
Volume 52, Issue 3 , Pages 450-451, March 2010

International Hepatology

  • Shannon S. Glaser

      Affiliations

    • Scott & White Digestive Disease Research Center, Scott & White Hospital, Temple, TX 76504, USA
    • Department of Medicine, Division of Gastroenterology, Scott & White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX 76504, USA
    • Corresponding Author InformationCorresponding author. Address: Department of Medicine, Scott & White and Texas A&M Health Science Center, Digestive Disease Research Center, 702 SW H.K. Dodgen Loop, Temple, TX 76504, USA. Tel.: +1 254 742 7058; fax: +1 254 724 9278.
    • ,
  • Gianfranco Alpini

      Affiliations

    • Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA
    • Scott & White Digestive Disease Research Center, Scott & White Hospital, Temple, TX 76504, USA
    • Department of Medicine, Division of Gastroenterology, Scott & White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, TX 76504, USA

Received 11 November 2009; received in revised form 19 November 2009; accepted 20 November 2009. published online 06 January 2010.

Article Outline

COMMENTARY ON

Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation.

Lüdtke TH, Christoffels VM, Petry M, Kispert A. Hepatology 2009 Mar;49:969–78, PMID: 19140222. Reprinted with permission of John Wiley & Sons, Inc. Copyright Hepatology, 2009.

Abstract

After specification of the hepatic endoderm, mammalian liver organogenesis progresses through a series of morphological stages that culminate in the migration of hepatocytes into the underlying mesenchyme to populate the hepatic lobes. Here, we show that in the mouse the transcriptional repressor Tbx3, a member of the Tbox protein family, is required for the transition from a hepatic diverticulum with a pseudo-stratified epithelium to a cell-emergent liver bud. In Tbx3-deficient embryos, proliferation in the hepatic epithelium is severely reduced, hepatoblasts fail to delaminate, and cholangiocyte rather than hepatocyte differentiation occurs. Molecular analyses suggest that the primary function of Tbx3 is to maintain expression of hepatocyte transcription factors, including hepatic nuclear factor 4a (Hnf4a) and CCAAT/enhancer binding protein (C/EBP), alpha (Cebpa), and to repress expression of cholangiocyte transcriptionfactors such as Onecut1 (Hnf6) and Hnf1b.

Conclusion

Tbx3 controls liver bud expansion by suppressing cholangiocyte and favoring hepatocyte differentiation in the liver bud.

Keywords: Tbx3, Cholangiocytes, Hepatocytes, Liver development

 

Recently, increased exploration for liver stem/progenitor cells and the localization of the stem cell niche in the liver has prompted renewed interest in the factors that regulate expansion of hepatocytes and cholangiocytes from bipotential hepatoblast precursor cells during embryonic development. In their publication in Hepatology, Lüdtke and colleagues examined the role of Tbx3, a member of the T-box protein family, in the regulation of liver bud expansion during mouse development [1. The time frame for the segregation of hepatobiliary lineages has not been accurately determined especially for cholangiocytes since the mechanisms are poorly understood and biliary fate determination does not occur in a single developmental phase [2. Of particular importance, this manuscript begins to address the mechanisms that determine hepatoblast cell fate between hepatocyte and cholangiocyte lineages.

T-box genes were originally described by geneticists in 1927 with the discovery of a mutation, Brachyury, (or T, for short tail), which results in a short tail phenotype in mice [3. The T gene required in mesoderm formation was cloned in 1990 [4. T-box genes participate in the regulation of diverse functions in development and mutations in T-box genes have been linked to a number of human disorders and diseases [5]. T-box genes have been extensively studied during cardiac development, which is regulated by multiple T-box genes in a complex mechanism exhibiting temporal and spatial regulation of the developing heart [6]. Recent evidence from Suzuki and colleagues has provided support for the involvement of Tbx3 in hepatogenesis [7]. They demonstrated that Tbx3 is expressed by multipotent hepatic progenitor cells that were isolated from developing mouse liver [7]. The deletion of Tbx3 also resulted in the increased expression of the tumor suppressor gene p19ARF (Cdkn2a), which promoted growth arrest in hepatoblasts and initiated cholangiocyte differentiation [7].

In their recent publication, Lüdtke and colleagues definitively demonstrate that Tbx3 promotes liver bud expansion in Tbx3 mutant mice [1]. The authors demonstrate that Tbx3 is strongly expressed in the liver bud during the expansion of the phase [1]. In the Tbx3-deficient embryos, the expansion of the hepatic epithelium was characterized by a reduction in the expression of the hepatoblast marker gene alpha fetoprotein and the hepatocyte marker albumin. However, there was an increased expression of the cholangiocyte-specific marker CK19 in 10–20% of the cells in the hypoplastic mutant livers [1]. These data indicate that lack of Tbx3 altered the lineage decision in hepatoblasts and shifted cell fate towards cholangiocytes at the expense of hepatocytes. In contrast to the findings of Suzuki, et al., there was no apparent involvement of cell-cycle regulators such as p19ARF in Tbx3 mutant mice [1]. Tbx3 seems to regulate hepatic development by suppressing cholangiocyte differentiation at E9.5 [1]. Interestingly, in addition to its role in cell fate determination, Tbx3 plays a crucial role in hepatoblast migration, which it most likely regulates through the expression of prospero-related homeobox 1 (Prox-1) [1]. At the molecular level, the data presented suggest that the primary role of Tbx3 is to maintain the expression of hepatocyte transcription factors (such as hepatic nuclear factor 4a (Hnf4a) and CCAAT/enhancer binding protein (C/EBP) and to repress the expression of cholangiocyte differentiation transcription factors (such as, Onecut1 (Hnf6) and Hnf1b) [1]. The exact mechanisms for the maintenance of hepatocyte transcription factors and repression of cholangiocyte transcription factors still need to be elucidated. Since Tbx3 is a transcriptional repressor, the maintenance of hepatocyte differentiation factors would require a mediator of some sort, while functioning to repress cholangiocyte transcription factors fits well with the role of Tbx3 in other systems [8]. Future studies will be required to elucidate this intricate temporal-spatial pattern of Tbx3 that occurs in embryonic liver development.

Lüdtke and colleagues also bring to the forefront the potential role that Tbx3 plays in liver regeneration and disease pathogenesis. In particular, one would postulate that Tbx3 plays a beneficial role in the regulation of hepatocyte regeneration following surgical resection and in response to hepatocellular damage. However, aberrant expression of Tbx3 in hepatocytes may impact carcinogenesis. In fact, Tbx3 and the closely related Tbx2 are over-expressed in several cancers including ovarian, breast, pancreatic, cervical, and melanoma cancers. In melanoma, over-expression of Tbx2 and Tbx3 leads to the down-regulation of E-cadherin expression and enhances cell migration along with the inhibition of senescence through the repression of p21CIP1 [9]. In mouse and human liver samples and cell lines, Tbx3 was implicated as a gene downstream of the Wnt/β-catenin pathway [10]. The over-expression of Tbx3 in hepatocellular carcinomas and hepatoblastomas was associated with the mutational status of β-catenin [10]. In fact, hepatoblastomas with marked over-expression of Tbx3 were resistant to chemotherapy and linked to unfavorable patient outcome [10]. To date, no studies have addressed the potential role of Tbx3 over-expression in cholangiocarcinoma. Expression of Tbx3 in cholangiocarcinoma may result in the alteration of the differentiation status of the cells, potentially maintaining to a minimum the de-differentiation of cholangiocytes towards a hepatocyte phenotype. Many questions about the regulatory mechanisms of Tbx3 during liver development and regeneration, as well as their potential involvement in liver cancer remain to be addressed in future studies. The elucidation of the fundamental mechanisms that regulate liver development is critical for understanding key concepts such as regeneration following surgical resection, disease processes and potentially the neoplastic transformation of hepatocytes and cholangiocytes.

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References 

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  9. Rodriguez M, Aladowicz E, Lanfrancone L, Goding CR. Tbx3 represses E-cadherin expression and enhances melanoma invasiveness. Cancer Res. 2008;68:7872–7881
  10. Renard CA, Labalette C, Armengol C, Cougot D, Wei Y, Cairo S, et al. Tbx3 is a downstream target of the Wnt/beta-catenin pathway and a critical mediator of beta-catenin survival functions in liver cancer. Cancer Res. 2007;67:901–910

PII: S0168-8278(09)00797-1

doi:10.1016/j.jhep.2009.11.021

Journal of Hepatology
Volume 52, Issue 3 , Pages 450-451, March 2010

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