Foxa1 and Foxa2 regulate bile duct development in mice
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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]”
From Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli (2014) · cites this paper as [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)
- PMC
- PMC2689124
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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