Cited by 131Liver physiology and pathologyPediatric Hepatobiliary Diseases and TreatmentsDevelopmental Biology and Gene Regulation

Foxa1 and Foxa2 regulate bile duct development in mice

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Li, Zhaoyu, White, Peter, Tuteja, Geetu, Rubins, Nir, Sackett, Sara, Kaestner, Klaus H.·2009·Journal of Clinical Investigation

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.

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  • Hepatocyte IL-6 production may also be important for signaling to other hepatic cell types such as bile duct epithelium cells.

    “although production by hepatocytes may also be important for signaling to other hepatic cell types such as the bile duct epithelium cells [27]”

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Authors
Li, Z., White, P., Tuteja, G., Rubins, N., Sackett, S., & Kaestner, K. H.
Affiliations
  • University of Pennsylvania (US)
  • Nationwide Children's Hospital (US)
Corresponding author
Kaestner, Klaus H.
Venue
Journal of Clinical Investigation
Published
2009-06-01
Volume
119
Issue
6
Pages
1537-1545
ISSN
0021-9738 (ISSN-L)
OpenAlex
W1994946944
Cited by
131
References
56
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 7 · 2022: 7 · 2021: 6 · 2020: 10 · 2019: 8 · 2018: 5 · 2017: 12 · 2016: 7 · 2015: 9 · 2014: 13 · 2013: 8 · 2012: 5
FWCI
7.35
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion)
Funders
  • University of Pennsylvania
  • U.S. Public Health Service (P01-049210)
  • Natural Sciences and Engineering Research Council of Canada
  • National Institute of Diabetes and Digestive and Kidney Diseases
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
FOXA1, FOXA2, bile duct development, cholangiocytes, cholangiocyte proliferation, interleukin-6, glucocorticoid receptor, transcriptional regulation, liver development, conditional gene deletion, biliary hyperplasia, foregut endoderm
MeSH terms
Animals, Bile Duct Diseases, Bile Ducts, Cell Differentiation, Fibrosis, Hyperplasia, Liver, Mice, Inbred C57BL, Receptors, Glucocorticoid, Interleukin-6, Mice, Knockout, Hepatocytes, Microscopy, Electron, Transmission, Cell Proliferation, Mice, Hepatocyte Nuclear Factor 3-alpha, Hepatocyte Nuclear Factor 3-beta

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