Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts
Open accessAbstract
In developing liver, cholangiocytes derive from the hepatoblasts and organize to form the bile ducts. Earlier work has shown that the SRY-related High Mobility Group box transcription factor 9 (SOX9) is transiently required for bile duct development, raising the question of the potential involvement of other SOX family members in biliary morphogenesis. Here we identify SOX4 as a new regulator of cholangiocyte development. Liver-specific inactivation of SOX4, combined or not with inactivation of SOX9, affects cholangiocyte differentiation, apico-basal polarity and bile duct formation. Both factors cooperate to control the expression of mediators of the Transforming Growth Factor-β, Notch, and Hippo-Yap signaling pathways, which are required for normal development of the bile ducts. In addition, SOX4 and SOX9 control formation of primary cilia, which are known signaling regulators. The two factors also stimulate secretion of laminin α5, an extracellular matrix component promoting bile duct maturation. We conclude that SOX4 is a new regulator of liver development and that it exerts a pleiotropic control on bile duct development in cooperation with SOX9.
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SCENIC+ analysis revealed 180 eRegulons, including SPI1, JDP2, RUNX1 in Kupffer cells; EBF1 and PAX5 in B cells; GATA3 and LEF1 in T cells; GATA4, MEIS1 and MAF in LSECs; LHX2 and TEAD1 in HSCs; WT1 in fibroblasts; and TEAD4, DOX4 and HNF1B in BECs, among others, in agreement with literature.
“This analysis revealed 180 eRegulons, including SPI1, JDP2, RUNX1 in Kupffer cells; EBF1 and PAX5 in B cells; GATA3 and LEF1 in T cells; GATA4, MEIS1 and MAF in LSECs; LHX2 and TEAD1 in HSCs; WT1 in fibroblasts; and TEAD4, DOX4 and HNF1B in BECs, among others, and in agreement with literature15–20.”
From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [20]
This approach identified PU.1, Runx, and Irf as candidate TFs for Kupffer cell enhancers; Pax5 and Ebf1 for B cells; Tbx21 for T cells; Meis1, Maf and Gata4 for LSECs; Mef2c and Lhx2 for HSC; and Tead4, Sox9 and Hnf1b for BECs.
“this approach identified PU.1, Runx, and Irf as candidate TFs for Kupffer cell enhancers37; Pax5 and Ebf1 for B cells38; Tbx21 for T cells39; Meis1, Maf and Gata4 for LSECs40; Mef2c and Lhx2 for HSC41; and Tead4, Sox9 and Hnf1b for BECs42”
From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [42]
Cites
Hippo Pathway Activity Influences Liver Cell Fate
Yimlamai, D., Christodoulou, C., Galli, G. G., Yanger, K., Pepe-Mooney, B., Gurung, B., Shrestha, K., Cahan, P., Stanger, B. Z., & Camargo, F. D. (2014) · Cell · doi:10.1016/j.cell.2014.03.060 · Cited by 857 · see citing works
Lüdtke, T. H. ‐., Christoffels, V. M., Petry, M., & Kispert, A. (2009) · Hepatology · doi:10.1002/hep.22700 · Cited by 117 · cited 1× · see citing works
“The scheme integrates data from references (Clotman et al., 2005; Clotman et al., 2002; Geisler et al., 2008; Hunter et al., 2007; Krupczak-Hollis et al., 2004; Ludtke et al., 2009; Oikawa et al., 2009; Rogler et al., 2009; Takayama et al., 2014; Tanimizu and Miyajima, 2004; Tanimizu et al., 2007; Tchorz et al., 2009;…”
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Maladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis
Zhu, C., Tabas, I., Schwabe, R. F., & Pajvani, U. B. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00365-6 · Cited by 112 · see citing works
Bravo González-Blas, C., Matetovici, I., Hillen, H., Taskiran, I. I., Vandepoel, R., Christiaens, V., Sansores-García, L., Verboven, E., Hulselmans, G., Poovathingal, S., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-023-01316-4 · Cited by 85 · see citing works
“…analysis revealed 180 eRegulons, including SPI1, JDP2, RUNX1 in Kupffer cells; EBF1 and PAX5 in B cells; GATA3 and LEF1 in T cells; GATA4, MEIS1 and MAF in LSECs; LHX2 and TEAD1 in HSCs; WT1 in fibroblasts; and TEAD4, DOX4 and HNF1B in BECs, among others, and in agreement with literature 15–20 .”
Generation of human adult hepatocyte organoids with metabolic functions
Igarashi, R., Oda, M., Okada, R., Yano, T., Takahashi, S., Pastuhov, S., Matano, M., Masuda, N., Togasaki, K., Ohta, Y., et al. (2025) · Nature · doi:10.1038/s41586-025-08861-y · Cited by 85 · see citing works
Fetal liver development and implications for liver disease pathogenesis
Lotto, J., Stephan, T. L., & Hoodless, P. A. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00775-2 · Cited by 47 · see citing works
Signalling pathways and transcriptional regulators orchestrating liver development and cancer
Campbell, S. A., Stephan, T. L., Lotto, J., Cullum, R., Drissler, S., & Hoodless, P. A. (2021) · Development · doi:10.1242/dev.199814 · Cited by 22 · see citing works
Enhancer grammar of liver cell types and hepatocyte zonation states
González-Blas, C. B., Matetovici, I., Hillen, H., Taskiran, I. I., Vandepoel, R., Christiaens, V., Sansores-García, L., Verboven, E., Hulselmans, G., Poovathingal, S., et al. (2022) · doi:10.1101/2022.12.08.519575 · Cited by 5 · see citing works
- Authors
- Poncy, A., Antoniou, A., Cordi, S., Pierreux, C. E., Jacquemin, P., & Lemaigre, F. P.
- Affiliations
- de Duve Institute (BE)
- Corresponding author
- Lemaigre, Frédéric P.
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 404
- Issue
- 2
- Pages
- 136-148
- ISSN
- 0012-1606 (ISSN-L)
- OpenAlex
- W1826646122
- Cited by
- 125
- References
- 2
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 14 · 2023: 11 · 2022: 8 · 2021: 14 · 2020: 13 · 2019: 11 · 2018: 10 · 2017: 16 · 2016: 9 · 2015: 2
- FWCI
- 7.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Digital Access to Libraries (submittedVersion)
- Funders
- Interuniversity Attraction Pole Programme (Belgian Science Policy
- D.G. Higher Education and Scientific Research
- French Community of Belgium (ARC 10/15-029)
- Commission of the European Communities (238821)
- Alphonse (3.4536.1)
- Jean Forton Fund, the Université Catholique de Louvain and the F.R.S.-FNRS (J.0058.15)
- CEP and PJ are research associates of the F.R.S.-FNRS
- 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
- SOX4, SOX9, bile duct development, cholangiocytes, hepatoblasts, liver development, apical-basal polarity, primary cilia, laminin alpha5, extracellular matrix, TGF-beta signaling, Notch signaling, Hippo/YAP signaling, transcription factors
- MeSH terms
- Hippo Signaling Pathway, YAP-Signaling Proteins, Animals, Bile Ducts, Intrahepatic, Cell Differentiation, Cells, Cultured, Laminin, Phosphoproteins, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Mice, Knockout, Gene Expression Regulation, Developmental, Cell Cycle Proteins, Organogenesis, Adaptor Proteins, Signal Transducing, Mice, Receptors, Notch, SOXC Transcription Factors, SOX9 Transcription Factor
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