Foxa1 and Foxa2 regulate bile duct development in mice
Zhaoyu Li, … , Sara Sackett, Klaus H. Kaestner
Zhaoyu Li, … , Sara Sackett, Klaus H. Kaestner
Published May 11, 2009
Citation Information: J Clin Invest. 2009;119(6):1537-1545. https://doi.org/10.1172/JCI38201.
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Research Article Hepatology

Foxa1 and Foxa2 regulate bile duct development in mice

Abstract

The forkhead box proteins A1 and A2 (Foxa1 and Foxa2) are transcription factors with critical roles in establishing the developmental competence of the foregut endoderm and in initiating liver specification. Using conditional gene ablation during a later phase of liver development, we show here that deletion of both Foxa1 and Foxa2 (Foxa1/2) in the embryonic liver caused hyperplasia of the biliary tree. Abnormal bile duct formation in Foxa1/2-deficient liver was due, at least in part, to activation of IL-6 expression, a proliferative signal for cholangiocytes. The glucocorticoid receptor is a negative regulator of IL-6 transcription; in the absence of Foxa1/2, the glucocorticoid receptor failed to bind to the IL-6 promoter, causing enhanced IL-6 expression. Thus, after liver specification, Foxa1/2 are required for normal bile duct development through prevention of excess cholangiocyte proliferation. Our data suggest that Foxa1/2 function as terminators of bile duct expansion in the adult liver through inhibition of IL-6 expression.

Authors

Zhaoyu Li, Peter White, Geetu Tuteja, Nir Rubins, Sara Sackett, Klaus H. Kaestner

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Figure 6

Foxa1/2 and GR corporately regulate IL-6 transcription.

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Foxa1/2 and GR corporately regulate IL-6 transcription. (A) Hepatic mRNA...
(A) Hepatic mRNA levels of NF-κB (p50), GR, and IL-6 receptor gp80 and gp130 subunits from 3-month-old Foxa1loxP/loxPFoxa2loxP/loxP and Foxa1loxP/loxPFoxa2loxP/loxPAlfpCre mice by real-time qRT-PCR. (B) ChIP assays for the occupancy of Foxa1/2, GR, and NF-κB on the mouse IL-6 promoter. (C) Hepatic mRNA levels from Foxa1, Foxa2, Il6, Nfkb (p50), and GR from wild-type mice after sham or BDL for 5 days, as assessed by real-time qRT-PCR. *P < 0.05 compared with sham-treated mice. (D) Model for the control of IL-6 transcription by Foxa1/2, GR and NF-κB. Green arrows indicate translational start sites. Top panel shows that GR-mediated IL-6 inhibition is dependent on Foxa1/2 occupancy. Bottom panel shows that once Foxa1/2 is deleted, NF-κB replaces the GR to bind to the IL-6 promoter and initiate IL-6 expression.