Rank-dependent control of tuft and BEST4 cell development in the intestine

Reegan J Willms; Tori McCabe; Lena Ocampo Jones; Ruth Schade; Edan Foley

doi:10.1038/s41467-026-73293-9

Rank-dependent control of tuft and BEST4 cell development in the intestine

Reegan J Willms
, Tori McCabe
, Lena Ocampo Jones
, Ruth Schade
, Edan Foley

University of Alberta
Department of Medical Microbiology and Immunology
Stanford University
Women and Children's Health Research Institute
Cancer Research Institute of Northern Alberta
Li Ka Shing Institute of Virology Department of Cell Biology
Department of Cell Biology University of Alberta

Research output: Contribution to journal › Article › peer-review

1 Citation (SciVal)

Abstract

Specialist intestinal epithelial cells are critical for barrier integrity and immune responses at the mucosal boundary, yet the pathways that govern their development are incompletely defined. Here, we identify an essential role for TNFRSF11A/RANK in shaping intestinal epithelial specialization in zebrafish. Using lineage trajectory analysis, we identify two tuft cell subtypes, including a subtype enriched for expression of genes required to produce pro-inflammatory leukotrienes. We show that RANK deficiency reduces the abundance of immune-regulatory tuft and BEST4 cells, increases goblet cell frequency, and promotes the accumulation of pro-inflammatory leukocytes in the gut. Functionally, we demonstrate that the number of cells expressing the BEST4 cell marker cftr expand following infection with a pandemic strain of Vibrio cholerae, and we show that RANK deficiency enhances fish susceptibility to host colonization by Vibrio, implicating this lineage in host defenses against an enteric pathogen. Together, our findings implicate RANK signaling in intestinal epithelial diversification and immune regulation.

Original language	English
Article number	6609
Journal	Nature Communications
Volume	17
Issue number	1
Early online date	19 May 2026
DOIs	https://doi.org/10.1038/s41467-026-73293-9
Publication status	Published - 19 May 2026

Data Availability Statement

The Bulk RNA-seq data generated in this study have been deposited in the NCBI GEO database under accession code GSE303709. The single cell RNA-seq data used in this study were deposited previously in the NCBI GEO database under accession code GSE230044 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE230044. Source data are provided with this paper.

Acknowledgements

We are very grateful to Dr. Jeffrey Farrell at the NIH for constructive feedback on this manuscript, and to Dr. Jennifer Hocking at the University of Alberta for expert guidance on zebrafish handling. We would also like to thank the University of Alberta North Campus Animal Services for their excellent care of the zebrafish aquatics facilities at the University of Alberta. Imaging experiments were performed at the University of Alberta Faculty of Medicine & Dentistry (FoMD) Cell Imaging Core, RRID:SCR_019200, which receives financial support from FoMD, the Department of Medical Microbiology and Immunology, the University Hospital Foundation, and Canada Foundation for Innovation (CFI) awards to contributing investigators. Immunohistochemistry experiments were performed at the University of Alberta’s Faculty of Science Department of Biological Sciences Advanced Microscopy Facility. The Advanced Microscopy Facility is supported by Alberta Innovation and Science, Canadian Foundation for Innovation, National Science and Engineering Research Council, University of Alberta, and Faculty of Science. This work used computing resources provided by the Stanford Genetics Bioinformatics Service Center.

Funding

This work was supported by a grant from the Canadian Institutes of Health Research (grant no. MOP77746) to EF. RJW received funding support through the National Science and Engineering Research Council Graduate Scholarships, and Alberta Innovates Graduate Student Scholarships.

Funders	Funder number
Natural Sciences and Engineering Research Council of Canada
Alberta Innovates
Canadian Institutes of Health Research	MOP77746

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/s41467-026-73293-9Licence: CC BY

Cite this

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Rank-dependent control of tuft and BEST4 cell development in the intestine

Abstract

Data Availability Statement

Acknowledgements

Funding

ASJC Scopus subject areas

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