Temporal Notch signaling and Hes-mediated competitive de-repression regulate mucociliary cell fates in Xenopus

Temporal Notch signaling and Hes-mediated competitive de-repression regulate mucociliary cell fates in Xenopus | bioRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results Temporal Notch signaling and Hes-mediated competitive de-repression regulate mucociliary cell fates in Xenopus View ORCID Profile Magdalena Maria Brislinger-Engelhardt , View ORCID Profile Mona Hansen , View ORCID Profile Tim Litwin , Maximilian Haas , Aisha Andricek , Fabian Lorenz , View ORCID Profile Africa Temporal-Plo , View ORCID Profile Sarah Bowden , View ORCID Profile Sandra Hägele , View ORCID Profile Damian Weber , View ORCID Profile Alexia Tasca , View ORCID Profile Stefan Haug , View ORCID Profile Clemens Kreutz , View ORCID Profile Peter Walentek doi: https://doi.org/10.1101/2023.02.15.528675 Magdalena Maria Brislinger-Engelhardt 1 Internal Medicine IV, Medical Center - University of Freiburg , Hugstetter Strasse 55, 79106 Freiburg, Germany 2 CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg , Schänzlestrasse 18, 79104 Freiburg, Germany 3 SGBM Spemann Graduate School for Biology and Medicine, University of Freiburg , Albertstrasse 19A, 79104 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Magdalena Maria Brislinger-Engelhardt Mona Hansen 1 Internal Medicine IV, Medical Center - University of Freiburg , Hugstetter Strasse 55, 79106 Freiburg, Germany 3 SGBM Spemann Graduate School for Biology and Medicine, University of Freiburg , Albertstrasse 19A, 79104 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Mona Hansen Tim Litwin 2 CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg , Schänzlestrasse 18, 79104 Freiburg, Germany 6 IMBI Institute of Medical Biometry and Statistics, Institute of Medicine and Medical Center Freiburg , Stefan-Meier Strasse 26, 79104 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Tim Litwin Maximilian Haas 1 Internal Medicine IV, Medical Center - University of Freiburg , Hugstetter Strasse 55, 79106 Freiburg, Germany 3 SGBM Spemann Graduate School for Biology and Medicine, University of Freiburg , Albertstrasse 19A, 79104 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Aisha Andricek 1 Internal Medicine IV, Medical Center - University of Freiburg , Hugstetter Strasse 55, 79106 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Fabian Lorenz 2 CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg , Schänzlestrasse 18, 79104 Freiburg, Germany 6 IMBI Institute of Medical Biometry and Statistics, Institute of Medicine and Medical Center Freiburg , Stefan-Meier Strasse 26, 79104 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Africa Temporal-Plo 1 Internal Medicine IV, Medical Center - University of Freiburg , Hugstetter Strasse 55, 79106 Freiburg, Germany 4 IMPRS-EBM International Max Planck Research School of Epigenetics , Biophysics, and Metabolism, Max Planck Institute of Immunobiology and Epigenetics , Stübeweg 51, 79108 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Africa Temporal-Plo Sarah Bowden 1 Internal Medicine IV, Medical Center - University of Freiburg , Hugstetter Strasse 55, 79106 Freiburg, Germany 2 CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg , Schänzlestrasse 18, 79104 Freiburg, Germany 4 IMPRS-EBM International Max Planck Research School of Epigenetics , Biophysics, and Metabolism, Max Planck Institute of Immunobiology and Epigenetics , Stübeweg 51, 79108 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sarah Bowden Sandra Hägele 1 Internal Medicine IV, Medical Center - University of Freiburg , Hugstetter Strasse 55, 79106 Freiburg, Germany 3 SGBM Spemann Graduate School for Biology and Medicine, University of Freiburg , Albertstrasse 19A, 79104 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sandra Hägele Damian Weber 1 Internal Medicine IV, Medical Center - University of Freiburg , Hugstetter Strasse 55, 79106 Freiburg, Germany 3 SGBM Spemann Graduate School for Biology and Medicine, University of Freiburg , Albertstrasse 19A, 79104 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Damian Weber Alexia Tasca 1 Internal Medicine IV, Medical Center - University of Freiburg , Hugstetter Strasse 55, 79106 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Alexia Tasca Stefan Haug 5 Institute of Genetic Epidemiology, Medical Center - University of Freiburg , Hugstetter Strasse 55, 79106 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Stefan Haug Clemens Kreutz 2 CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg , Schänzlestrasse 18, 79104 Freiburg, Germany 6 IMBI Institute of Medical Biometry and Statistics, Institute of Medicine and Medical Center Freiburg , Stefan-Meier Strasse 26, 79104 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Clemens Kreutz Peter Walentek 1 Internal Medicine IV, Medical Center - University of Freiburg , Hugstetter Strasse 55, 79106 Freiburg, Germany 2 CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg , Schänzlestrasse 18, 79104 Freiburg, Germany 3 SGBM Spemann Graduate School for Biology and Medicine, University of Freiburg , Albertstrasse 19A, 79104 Freiburg, Germany 4 IMPRS-EBM International Max Planck Research School of Epigenetics , Biophysics, and Metabolism, Max Planck Institute of Immunobiology and Epigenetics , Stübeweg 51, 79108 Freiburg, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Peter Walentek For correspondence: peter.walentek{at}medizin.uni-freiburg.de Abstract Full Text Info/History Metrics Supplementary material Preview PDF Abstract Mucociliary epithelia are found across different organs in animals, where they release bioactive substances and generate extracellular fluid flows. One key function of mucociliary epithelia is the clearance of pathogens, e.g. in the vertebrate lung and the epidermis of amphibian tadpoles. Mucociliary clearance relies on the correct balance between secretory cells that release mucus, ciliated cells that generate fluid flow as well as specialized cell types, including pH-regulating ionocytes and basal stem cells. Notch signaling, Hes repressors and cell type-inducing transcription factors (e.g. Foxi1, Mcidas, Spdef and Tp63) regulate cell fates and cell type proportions across mucociliary systems. Lateral inhibition was proposed to control mucociliary cell fates, but current models cannot explain how more than two cell types are generated and how Hes genes are employed as mediators during patterning. Using the Xenopus tadpole epidermis, we addressed these open questions in mucociliary biology through a combination of in vivo and organoid experiments, time-resolved transcriptomic studies and mathematical modeling. This revealed that ionocytes, ciliated cells, secretory cells and basal cells are preferentially specified at different time points and Notch signaling levels via sequentially expressed Hes factors. We termed this mode of patterning “competitive de-repression”, because cell fates are selected by suppression of alternative fate choices, and demonstrate that this relies on differential active repression of cell fate transcription factors. Mathematical modeling further indicated the need for a positively Notch-regulated patterning factor, and we provide evidence that Spdef mediates Notch input for secretory and basal cell specification. Collectively, this work presents a coherent model for Notch- and Hes-mediated mucociliary cell fate specification in a vertebrate tissue, which allows for the specification of more than two cell fates within the Notch lateral-inhibition paradigm. Competing Interest Statement The authors have declared no competing interest. Footnotes Data on temporal patterning, generation of ligand-expressing cells, Hes and Spdef functions and mathematical model improvement. Funder Information Declared Deutsche Forschungsgemeinschaft , WA3365/2-1 , WA3365/5-1 , WA3365/4-1 , 431984000 , 390939984 NIH Common Fund , K99HL127275 European Research Council , 101170596 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Back to top Previous Next Posted March 16, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Share Temporal Notch signaling and Hes-mediated competitive de-repression regulate mucociliary cell fates in Xenopus Magdalena Maria Brislinger-Engelhardt , Mona Hansen , Tim Litwin , Maximilian Haas , Aisha Andricek , Fabian Lorenz , Africa Temporal-Plo , Sarah Bowden , Sandra Hägele , Damian Weber , Alexia Tasca , Stefan Haug , Clemens Kreutz , Peter Walentek bioRxiv 2023.02.15.528675; doi: https://doi.org/10.1101/2023.02.15.528675 Share This Article: Copy Citation Tools Temporal Notch signaling and Hes-mediated competitive de-repression regulate mucociliary cell fates in Xenopus Magdalena Maria Brislinger-Engelhardt , Mona Hansen , Tim Litwin , Maximilian Haas , Aisha Andricek , Fabian Lorenz , Africa Temporal-Plo , Sarah Bowden , Sandra Hägele , Damian Weber , Alexia Tasca , Stefan Haug , Clemens Kreutz , Peter Walentek bioRxiv 2023.02.15.528675; doi: https://doi.org/10.1101/2023.02.15.528675 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Developmental Biology Subject Areas All Articles Animal Behavior and Cognition (8003) Biochemistry (18709) Bioengineering (14841) Bioinformatics (44360) Biophysics (22560) Cancer Biology (19680) Cell Biology (26844) Clinical Trials (138) Developmental Biology (13942) Ecology (20969) Epidemiology (2067) Evolutionary Biology (25412) Genetics (16151) Genomics (23477) Immunology (18678) Microbiology (42413) Molecular Biology (18021) Neuroscience (93343) Paleontology (699) Pathology (2977) Pharmacology and Toxicology (5086) Physiology (8105) Plant Biology (15969) Scientific Communication and Education (2094) Synthetic Biology (4549) Systems Biology (10219) Zoology (2384)

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