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Cell Rep. 2019 Sep 24;28(13):3338-3352.e6. doi: 10.1016/j.celrep.2019.08.063.

ΔN-Tp63 Mediates Wnt/β-Catenin-Induced Inhibition of Differentiation in Basal Stem Cells of Mucociliary Epithelia.

Author information

1
Internal Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Systems Biological Analysis, Albert Ludwigs University Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, Albert Ludwigs University Freiburg, Freiburg, Germany.
2
Internal Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Systems Biological Analysis, Albert Ludwigs University Freiburg, Freiburg, Germany.
3
Genetics, Genomics and Development Division, Molecular and Cell Biology Department, University of California, Berkeley, Berkeley, CA, USA.
4
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
5
Internal Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Systems Biological Analysis, Albert Ludwigs University Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, Albert Ludwigs University Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, Albert Ludwigs University Freiburg, Freiburg, Germany.
6
Transcriptome and Genome Core Unit, University Medical Center Göttingen, Göttingen, Germany.
7
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
8
Internal Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Systems Biological Analysis, Albert Ludwigs University Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, Albert Ludwigs University Freiburg, Freiburg, Germany; Genetics, Genomics and Development Division, Molecular and Cell Biology Department, University of California, Berkeley, Berkeley, CA, USA; CIBSS - Centre for Integrative Biological Signalling Studies, Albert Ludwigs University Freiburg, Freiburg, Germany. Electronic address: peter.walentek@medizin.uni-freiburg.de.

Abstract

Mucociliary epithelia provide a first line of defense against pathogens. Impaired regeneration and remodeling of mucociliary epithelia are associated with dysregulated Wnt/β-catenin signaling in chronic airway diseases, but underlying mechanisms remain elusive, and studies yield seemingly contradicting results. Employing the Xenopus mucociliary epidermis, the mouse airway, and human airway Basal cells, we characterize the evolutionarily conserved roles of Wnt/β-catenin signaling in vertebrates. In multiciliated cells, Wnt is required for cilia formation during differentiation. In Basal cells, Wnt prevents specification of epithelial cell types by activating ΔN-TP63, a master transcription factor, which is necessary and sufficient to mediate the Wnt-induced inhibition of specification and is required to retain Basal cells during development. Chronic Wnt activation leads to remodeling and Basal cell hyperplasia, which are reversible in vivo and in vitro, suggesting Wnt inhibition as a treatment option in chronic lung diseases. Our work provides important insights into mucociliary signaling, development, and disease.

KEYWORDS:

Wnt signaling; Xenopus; airway epithelia; basal cell; epithelia; mouse; mucociliary; multiciliated cell; β-catenin

PMID:
31553905
DOI:
10.1016/j.celrep.2019.08.063
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