IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-35963-w.html
   My bibliography  Save this article

Jag1-Notch cis-interaction determines cell fate segregation in pancreatic development

Author

Listed:
  • Xiaochan Xu

    (University of Copenhagen)

  • Philip Allan Seymour

    (University of Copenhagen
    University of Copenhagen)

  • Kim Sneppen

    (University of Copenhagen)

  • Ala Trusina

    (University of Copenhagen)

  • Anuska la Rosa Egeskov-Madsen

    (University of Copenhagen
    University of Copenhagen)

  • Mette Christine Jørgensen

    (University of Copenhagen
    University of Copenhagen)

  • Mogens Høgh Jensen

    (University of Copenhagen)

  • Palle Serup

    (University of Copenhagen
    University of Copenhagen)

Abstract

The Notch ligands Jag1 and Dll1 guide differentiation of multipotent pancreatic progenitor cells (MPCs) into unipotent pro-acinar cells (PACs) and bipotent duct/endocrine progenitors (BPs). Ligand-mediated trans-activation of Notch receptors induces oscillating expression of the transcription factor Hes1, while ligand-receptor cis-interaction indirectly represses Hes1 activation. Despite Dll1 and Jag1 both displaying cis- and trans-interactions, the two mutants have different phenotypes for reasons not fully understood. Here, we present a mathematical model that recapitulates the spatiotemporal differentiation of MPCs into PACs and BPs. The model correctly captures cell fate changes in Notch pathway knockout mice and small molecule inhibitor studies, and a requirement for oscillatory Hes1 expression to maintain the multipotent state. Crucially, the model entails cell-autonomous attenuation of Notch signaling by Jag1-mediated cis-inhibition in MPC differentiation. The model sheds light on the underlying mechanisms, suggesting that cis-interaction is crucial for exiting the multipotent state, while trans-interaction is required for adopting the bipotent fate.

Suggested Citation

  • Xiaochan Xu & Philip Allan Seymour & Kim Sneppen & Ala Trusina & Anuska la Rosa Egeskov-Madsen & Mette Christine Jørgensen & Mogens Høgh Jensen & Palle Serup, 2023. "Jag1-Notch cis-interaction determines cell fate segregation in pancreatic development," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35963-w
    DOI: 10.1038/s41467-023-35963-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-35963-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-35963-w?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. David Sprinzak & Amit Lakhanpal & Lauren LeBon & Leah A. Santat & Michelle E. Fontes & Graham A. Anderson & Jordi Garcia-Ojalvo & Michael B. Elowitz, 2010. "Cis-interactions between Notch and Delta generate mutually exclusive signalling states," Nature, Nature, vol. 465(7294), pages 86-90, May.
    2. Lauren E. Byrnes & Daniel M. Wong & Meena Subramaniam & Nathaniel P. Meyer & Caroline L. Gilchrist & Sarah M. Knox & Aaron D. Tward & Chun J. Ye & Julie B. Sneddon, 2018. "Lineage dynamics of murine pancreatic development at single-cell resolution," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    3. Hjalte List Larsen & Laura Martín-Coll & Alexander Valentin Nielsen & Christopher V. E. Wright & Ala Trusina & Yung Hae Kim & Anne Grapin-Botton, 2017. "Stochastic priming and spatial cues orchestrate heterogeneous clonal contribution to mouse pancreas organogenesis," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    4. Åsa Apelqvist & Hao Li & Lukas Sommer & Paul Beatus & David J. Anderson & Tasuku Honjo & Martin Hrabě de Angelis & Urban Lendahl & Helena Edlund, 1999. "Notch signalling controls pancreatic cell differentiation," Nature, Nature, vol. 400(6747), pages 877-881, August.
    5. Pau Formosa-Jordan & Marta Ibañes, 2014. "Competition in Notch Signaling with Cis Enriches Cell Fate Decisions," PLOS ONE, Public Library of Science, vol. 9(4), pages 1-14, April.
    6. Marissa A. Scavuzzo & Matthew C. Hill & Jolanta Chmielowiec & Diane Yang & Jessica Teaw & Kuanwei Sheng & Yuelin Kong & Maria Bettini & Chenghang Zong & James F. Martin & Malgorzata Borowiak, 2018. "Endocrine lineage biases arise in temporally distinct endocrine progenitors during pancreatic morphogenesis," Nature Communications, Nature, vol. 9(1), pages 1-21, December.
    7. David Willnow & Uwe Benary & Anca Margineanu & Maria Lillina Vignola & Fabian Konrath & Igor M. Pongrac & Zahra Karimaddini & Alessandra Vigilante & Jana Wolf & Francesca M. Spagnoli, 2021. "Quantitative lineage analysis identifies a hepato-pancreato-biliary progenitor niche," Nature, Nature, vol. 597(7874), pages 87-91, September.
    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. Zhuo Ma & Xiaofei Zhang & Wen Zhong & Hongyan Yi & Xiaowei Chen & Yinsuo Zhao & Yanlin Ma & Eli Song & Tao Xu, 2023. "Deciphering early human pancreas development at the single-cell level," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Jolanta Chmielowiec & Wojciech J. Szlachcic & Diane Yang & Marissa A. Scavuzzo & Katrina Wamble & Alejandro Sarrion-Perdigones & Omaima M. Sabek & Koen J. T. Venken & Malgorzata Borowiak, 2022. "Human pancreatic microenvironment promotes β-cell differentiation via non-canonical WNT5A/JNK and BMP signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Teodora Manea & Jessica Kristine Nelson & Cristina Maria Garrone & Karin Hansson & Ian Evans & Axel Behrens & Rocio Sancho, 2023. "USP7 controls NGN3 stability and pancreatic endocrine lineage development," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Sophie K Kay & Heather A Harrington & Sarah Shepherd & Keith Brennan & Trevor Dale & James M Osborne & David J Gavaghan & Helen M Byrne, 2017. "The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt," PLOS Computational Biology, Public Library of Science, vol. 13(2), pages 1-28, February.
    5. Mostafa Bakhti & Aimée Bastidas-Ponce & Sophie Tritschler & Oliver Czarnecki & Marta Tarquis-Medina & Eva Nedvedova & Jessica Jaki & Stefanie J. Willmann & Katharina Scheibner & Perla Cota & Ciro Sali, 2022. "Synaptotagmin-13 orchestrates pancreatic endocrine cell egression and islet morphogenesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Jennifer P. Nguyen & Timothy D. Arthur & Kyohei Fujita & Bianca M. Salgado & Margaret K. R. Donovan & Hiroko Matsui & Ji Hyun Kim & Agnieszka D’Antonio-Chronowska & Matteo D’Antonio & Kelly A. Frazer, 2023. "eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    7. Hwee Hui Lau & Nicole A. J. Krentz & Fernando Abaitua & Marta Perez-Alcantara & Jun-Wei Chan & Jila Ajeian & Soumita Ghosh & Yunkyeong Lee & Jing Yang & Swaraj Thaman & Benoite Champon & Han Sun & Alo, 2023. "PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    8. Sapna Puri & Hasna Maachi & Gopika Nair & Holger A. Russ & Richard Chen & Pamela Pulimeno & Zachary Cutts & Vasilis Ntranos & Matthias Hebrok, 2024. "Sox9 regulates alternative splicing and pancreatic beta cell function," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    9. Romana Bohuslavova & Valeria Fabriciova & Ondrej Smolik & Laura Lebrón-Mora & Pavel Abaffy & Sarka Benesova & Daniel Zucha & Lukas Valihrach & Zuzana Berkova & Frantisek Saudek & Gabriela Pavlinkova, 2023. "NEUROD1 reinforces endocrine cell fate acquisition in pancreatic development," Nature Communications, Nature, vol. 14(1), pages 1-20, 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:14:y:2023:i:1:d:10.1038_s41467-023-35963-w. 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.