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Arl13b controls basal cell stemness properties and Hedgehog signaling in the mouse epididymis

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Abstract

Epithelial cells orchestrate a series of intercellular signaling events in response to tissue damage. While the epididymis is composed of a pseudostratified epithelium that controls the acquisition of male fertility, the maintenance of its integrity in the context of tissue damage or inflammation remains largely unknown. Basal cells of the epididymis contain a primary cilium, an organelle that controls cellular differentiation in response to Hedgehog signaling cues. Hypothesizing its contribution to epithelial homeostasis, we knocked out the ciliary component ARL13B in keratin 5-positive basal cells. In this model, the reduced size of basal cell primary cilia was associated with impaired Hedgehog signaling and the loss of KRT5, KRT14, and P63 basal cell markers. When subjected to tissue injury, the epididymal epithelium from knock-out mice displayed imbalanced rates of cell proliferation/apoptosis and failed to properly regenerate in vivo. This response was associated with changes in the transcriptomic landscape related to immune response, cell differentiation, cell adhesion, and triggered severe hypoplasia of the epithelium. Together our results indicate that the ciliary GTPase, ARL13B, participates in the transduction of the Hedgehog signaling pathway to maintain basal cell stemness needed for tissue regeneration. These findings provide new insights into the role of basal cell primary cilia as safeguards of pseudostratified epithelia.

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Availability of data and materials

All data generated during this study are included in either the published article or its additional files. All raw data used for the microarray study can be found online on the Gene Expression Omnibus (GEO) repository (GSE206700).

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Acknowledgements

The authors would like to thank Sylvie Breton, Ph.D., for providing the V-ATPase and AQP9 antibody, Sabine Elowe, Ph.D., for providing access to the confocal microscope and Sonia Francoeur and Sophie Vachon for their technical support at the animal facility.

Funding

This work was supported by a CIHR operating grant and an FRQS-Junior 2 salary award to CB. LG is a recipient of FRQS, CRDSI, RQR and CHU Foundation fellowships. DGC is a recipient of CIHR operating Grant 84576 and funding from the FRQNT-Réseau de recherche en Reproduction.

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  1. Faculty of Medicine, Department of Obstetrics, Gynecology and Reproduction, Université Laval, CHU de Québec Research Center (CHUL), Quebec City, QC, Canada

    Laura Girardet, Daniel G. Cyr & Clémence Belleannée

  2. Laboratory for Reproductive Toxicology, INRS-Centre Armand-Frappier Santé Biotechnologie, Université du Québec, Laval, QC, Canada

    Daniel G. Cyr

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LG conducted the experiments, analysis and drafted the manuscript. DC and CB contributed to the study design and manuscript preparation. All authors have approved the final version and submission of this article.

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Correspondence to Clémence Belleannée.

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All experimental procedures involving mice were approved by the ethical committee of the Institutional Review Board of the Centre Hospitalier Universitaire de Québec (CHUQ; CPAC licenses 18-029 and 2016051-1, C. Belleannée) and were conducted in accordance with the requirements defined by the Guide for the Care and Use of Laboratory Animals. Mice were housed and reproduced in the elite animal facility of the CHU de Quebec research Center under a controlled lighting regimen (16 L: 8 D) at 21–22 °C and supplied with food and water ad libitum. Prior to dissection, animals were sacrificed via CO2 inhalation.

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Girardet, L., Cyr, D.G. & Belleannée, C. Arl13b controls basal cell stemness properties and Hedgehog signaling in the mouse epididymis. Cell. Mol. Life Sci. 79, 556 (2022). https://doi.org/10.1007/s00018-022-04570-1

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