The biliary system, pancreas and liver all develop from the nearby foregut at almost the same time in mammals. The molecular mechanisms that determine the identity of each organ in this complex area are unknown.

No abstract

Mice deficient in the nuclear factor B (NF-B)-transactivating gene RelA (p65) die at embryonic days 14 -15 with massive liver apoptosis. In the adult liver, activation of the NF-B heterodimer RelA/p50 can cause hepatocyte proliferation, apoptosis, or the induction of acute-phase response genes. We examined, during wild-type fetal liver development, the expression of the Rel family member proteins, as well as other proteins known to be important for NF-B activation. We found these proteins and active NF-B complexes in the developing liver from at least 2 days before the onset of lethality observed in RelA knockouts. This suggests that the timing of NF-B activation is not related to the timing of lethality. We therefore hypothesized that, in the absence of RelA, embryos were sensitized to tumor necrosis factor (TNF) receptor 1 (TNFR-1)-mediated apoptosis. Thus, we generated mice that were deficient in both RelA and TNFR-1 to determine whether apoptotic signaling through TNFR-1 was responsible for the lethal phenotype. RelA/TNFR-1 double knockout mice survived embryonic development and were born with normal livers without evidence of increased hepatocyte apoptosis. These animals became runted shortly after birth and survived an average of 10 days, dying from acute hepatitis with an extensive hepatic infiltration of immature neutrophils. We conclude that neither RelA nor TNFR-1 is required for liver development and that RelA protects the embryonic liver from TNFR-1-mediated apoptotic signals. However, the absence of both TNFR-1 signaling and RelA activity in newborn mice makes these animals susceptible to endogenous hepatic infection. The NF-B transcription factor modulates gene expression in many cellular responses, including inflammation, apoptosis, and liver regeneration.

No abstract

The expression of C/EBP␣, which may govern transcription of mature hepatocyte marker genes, was suppressed in periportal hepatoblasts in mouse liver development, leading to biliary cell differentiation. This study was undertaken to analyze how inactivation of the Cebpa gene affects biliary cell differentiation and gene expression of the regulatory genes for that differentiation, including Hnf1b and Hnf6. In the knockout mouse liver at midgestation stages, pseudoglandular structures were abundantly induced in the parenchyma with elevated expression of Hnf6 and Hnf1b mRNAs. The wild-type liver parenchyma expressed mRNAs of these transcription factors at low levels, though periportal biliary progenitors had strong expression of them. These results suggest that expression of Hnf6 and Hnf1b is downstream of C/EBP␣ action in fetal liver development, and that the suppression of C/EBP␣ expression in periportal hepatoblasts may lead to expression of Hnf6 and Hnf1b mRNAs. Immunohistochemical studies with biliary cell markers in knockout livers demonstrated that differentiated biliary epithelial cells were confined to around the portal veins. The suppression of C/EBP␣ expression may result in upregulation of Hnf6 and Hnf1b gene expression, but be insufficient for biliary cell differentiation. When liver fragments of Cebpa-knockout fetuses, in which hepatoblasts were contained as an endodermal component, were transplanted in the testis of Scid (Prkdc) male mice, almost all hepatoblasts gave rise to biliary epithelial cells. Wild-type hepatoblasts constructed mature hepatic tissue accompanied by biliary cell differentiation. These results also demonstrate that the suppression of C/EBP␣ expression may stimulate biliary cell differentiation. Development 133, 4233-4243 (2006) DEVELOPMENT 4234 their up-or downstream relationships with the action of C/EBP␣ in biliary cell differentiation. The knockout mice are neonatal lethal because of hypoglycemia accompanied by hyperammonemia (Flodby et al., 1996; Kimura et al., 1998;Wang et al., 1995). Thus, it is intriguing to study what type of histology the knockout liver exhibits and how biliary epithelial tissue is induced when the knockouts survive. In vitro studies have demonstrated that knockout hepatocytes can immortalize at a higher frequency (Soriano et al., 1998). KEY WORDS: C/EBP␣ ␣, Knockout, Hepatoblasts, Biliary epithelial cells, Bile ducts, Morphogenesis, MouseIn the present study, we demonstrate the expression of biliary cell markers in pseudoglandular cells of Cebpa-knockout livers. Inactivation of the Cebpa gene not only suppresses hepatocyte maturation, but also upregulates regulatory genes for biliary cell differentiation such as Hnf6 and Hnf1b genes in the liver parenchyma, suggesting that the absence of C/EBP␣ in normal biliary cells induces Hnf6 and Hnf1b expression, leading to biliary cell differentiation. Jag1 and Notch2 mRNAs were also upregulated in knockout livers, but not to the same extent as Hnf6 and Hnf1b mRNAs. Testicular transplants of the knockout livers...