IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56813-x.html
   My bibliography  Save this article

Sox9 inhibits Activin A to promote biliary maturation and branching morphogenesis

Author

Listed:
  • Hannah R. Hrncir

    (Emory University
    Emory University)

  • Brianna Goodloe

    (Emory University)

  • Sergei Bombin

    (Emory University)

  • Connor B. Hogan

    (Emory University)

  • Othmane Jadi

    (University of North Carolina at Chapel Hill)

  • Adam D. Gracz

    (Emory University
    Emory University)

Abstract

Intrahepatic bile duct (IHBD) development produces a morphologically heterogeneous network of large “ducts” and small “ductules” by adulthood. IHBD formation is closely linked to developmental specification of biliary epithelial cells (BECs) starting as early as E13.5, but mechanisms regulating differential IHBD morphology remain poorly understood. Here, we show that duct and ductule development has distinct genetic requirements, with Sox9 required to form the developmental precursors to peripheral ductules in adult livers. By optimizing large-volume IHBD imaging, we find that IHBDs emerge as a homogeneous webbed structure by E15.5 and undergo morphological maturation through 2 weeks of age. Developmental knockout of Sox9 leads to decreased postnatal branching morphogenesis, resulting in adult IHBDs with normal ducts but significantly fewer ductules. In the absence of Sox9, BECs fail to mature and exhibit elevated TGF-β signaling and Activin A. Exogenous Activin A is sufficient to induce developmental gene expression and morphological defects in wild-type BEC organoids, while early postnatal inhibition of Activin A in vivo rescues IHBD morphogenesis in the absence of Sox9. Our data demonstrate that proper IHBD architecture relies on inhibition of Activin A by Sox9 to promote ductule morphogenesis, defining regulatory mechanisms underlying morphological heterogeneity.

Suggested Citation

  • Hannah R. Hrncir & Brianna Goodloe & Sergei Bombin & Connor B. Hogan & Othmane Jadi & Adam D. Gracz, 2025. "Sox9 inhibits Activin A to promote biliary maturation and branching morphogenesis," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56813-x
    DOI: 10.1038/s41467-025-56813-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56813-x
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-56813-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Toshiro Sato & Robert G. Vries & Hugo J. Snippert & Marc van de Wetering & Nick Barker & Daniel E. Stange & Johan H. van Es & Arie Abo & Pekka Kujala & Peter J. Peters & Hans Clevers, 2009. "Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche," Nature, Nature, vol. 459(7244), pages 262-265, May.
    2. Kuhn, Max, 2008. "Building Predictive Models in R Using the caret Package," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 28(i05).
    3. Johanna R. Schaub & Kari A. Huppert & Simone N. T. Kurial & Bernadette Y. Hsu & Ashley E. Cast & Bryan Donnelly & Rebekah A. Karns & Feng Chen & Milad Rezvani & Hubert Y. Luu & Aras N. Mattis & Anne-L, 2018. "De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation," Nature, Nature, vol. 557(7704), pages 247-251, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Prabal Das & D. A. Sachindra & Kironmala Chanda, 2022. "Machine Learning-Based Rainfall Forecasting with Multiple Non-Linear Feature Selection Algorithms," Water Resources Management: An International Journal, Published for the European Water Resources Association (EWRA), Springer;European Water Resources Association (EWRA), vol. 36(15), pages 6043-6071, December.
    2. Paulo Infante & Gonçalo Jacinto & Anabela Afonso & Leonor Rego & Pedro Nogueira & Marcelo Silva & Vitor Nogueira & José Saias & Paulo Quaresma & Daniel Santos & Patrícia Góis & Paulo Rebelo Manuel, 2023. "Factors That Influence the Type of Road Traffic Accidents: A Case Study in a District of Portugal," Sustainability, MDPI, vol. 15(3), pages 1-16, January.
    3. Ephrem Habyarimana & Faheem S Baloch, 2021. "Machine learning models based on remote and proximal sensing as potential methods for in-season biomass yields prediction in commercial sorghum fields," PLOS ONE, Public Library of Science, vol. 16(3), pages 1-23, March.
    4. Crespo, Cristian, 2020. "Two become one: improving the targeting of conditional cash transfers with a predictive model of school dropout," LSE Research Online Documents on Economics 123139, London School of Economics and Political Science, LSE Library.
    5. Alexander Wettstein & Gabriel Jenni & Ida Schneider & Fabienne Kühne & Martin grosse Holtforth & Roberto La Marca, 2023. "Predictors of Psychological Strain and Allostatic Load in Teachers: Examining the Long-Term Effects of Biopsychosocial Risk and Protective Factors Using a LASSO Regression Approach," IJERPH, MDPI, vol. 20(10), pages 1-20, May.
    6. Tang, Kayu & Parsons, David J. & Jude, Simon, 2019. "Comparison of automatic and guided learning for Bayesian networks to analyse pipe failures in the water distribution system," Reliability Engineering and System Safety, Elsevier, vol. 186(C), pages 24-36.
    7. Daifeng Xiang & Gangsheng Wang & Jing Tian & Wanyu Li, 2023. "Global patterns and edaphic-climatic controls of soil carbon decomposition kinetics predicted from incubation experiments," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Joel Podgorski & Oliver Kracht & Luis Araguas-Araguas & Stefan Terzer-Wassmuth & Jodie Miller & Ralf Straub & Rolf Kipfer & Michael Berg, 2024. "Groundwater vulnerability to pollution in Africa’s Sahel region," Nature Sustainability, Nature, vol. 7(5), pages 558-567, May.
    9. Tranos, Emmanouil & Incera, Andre Carrascal & Willis, George, 2022. "Using the web to predict regional trade flows: data extraction, modelling, and validation," OSF Preprints 9bu5z, Center for Open Science.
    10. Štefan Lyócsa & Petra Vašaničová & Branka Hadji Misheva & Marko Dávid Vateha, 2022. "Default or profit scoring credit systems? Evidence from European and US peer-to-peer lending markets," Financial Innovation, Springer;Southwestern University of Finance and Economics, vol. 8(1), pages 1-21, December.
    11. Marcos Rodrigues & Fermín Alcasena & Pere Gelabert & Cristina Vega‐García, 2020. "Geospatial Modeling of Containment Probability for Escaped Wildfires in a Mediterranean Region," Risk Analysis, John Wiley & Sons, vol. 40(9), pages 1762-1779, September.
    12. Natalia Pardo-Lorente & Anestis Gkanogiannis & Luca Cozzuto & Antoni Gañez Zapater & Lorena Espinar & Ritobrata Ghose & Jacqueline Severino & Laura García-López & Rabia Gül Aydin & Laura Martin & Mari, 2024. "Nuclear localization of MTHFD2 is required for correct mitosis progression," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    13. Andrea Lazzari & Simone Giovinazzo & Giovanni Cabassi & Massimo Brambilla & Carlo Bisaglia & Elio Romano, 2025. "Evaluating Urban Sewage Sludge Distribution on Agricultural Land Using Interpolation and Machine Learning Techniques," Agriculture, MDPI, vol. 15(2), pages 1-13, January.
    14. Giovanny Pillajo-Quijia & Blanca Arenas-Ramírez & Camino González-Fernández & Francisco Aparicio-Izquierdo, 2020. "Influential Factors on Injury Severity for Drivers of Light Trucks and Vans with Machine Learning Methods," Sustainability, MDPI, vol. 12(4), pages 1-28, February.
    15. Zander S. Venter & Adam Sadilek & Charlotte Stanton & David N. Barton & Kristin Aunan & Sourangsu Chowdhury & Aaron Schneider & Stefano Maria Iacus, 2021. "Mobility in Blue-Green Spaces Does Not Predict COVID-19 Transmission: A Global Analysis," IJERPH, MDPI, vol. 18(23), pages 1-12, November.
    16. G. Brooke Anderson & Keith W. Oleson & Bryan Jones & Roger D. Peng, 2018. "Classifying heatwaves: developing health-based models to predict high-mortality versus moderate United States heatwaves," Climatic Change, Springer, vol. 146(3), pages 439-453, February.
    17. Van Belle, Jente & Guns, Tias & Verbeke, Wouter, 2021. "Using shared sell-through data to forecast wholesaler demand in multi-echelon supply chains," European Journal of Operational Research, Elsevier, vol. 288(2), pages 466-479.
    18. Jun Wang & Jinyong Huang & Yunlong Hu & Qianwen Guo & Shasha Zhang & Jinglin Tian & Yanqin Niu & Ling Ji & Yuzhong Xu & Peijun Tang & Yaqin He & Yuna Wang & Shuya Zhang & Hao Yang & Kang Kang & Xinchu, 2024. "Terminal modifications independent cell-free RNA sequencing enables sensitive early cancer detection and classification," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    19. Ali Al-Ramini & Mohammad A Takallou & Daniel P Piatkowski & Fadi Alsaleem, 2022. "Quantifying changes in bicycle volumes using crowdsourced data," Environment and Planning B, , vol. 49(6), pages 1612-1630, July.
    20. Enara Larrañaga & Miquel Marin-Riera & Aina Abad-Lázaro & David Bartolomé-Català & Aitor Otero & Vanesa Fernández-Majada & Eduard Batlle & James Sharpe & Samuel Ojosnegros & Jordi Comelles & Elena Mar, 2025. "Long-range organization of intestinal 2D-crypts using exogenous Wnt3a micropatterning," Nature Communications, Nature, vol. 16(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56813-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.