RNF43/ZNRF3 negatively regulates taste tissue homeostasis and positively regulates dorsal lingual epithelial tissue homeostasis

TY - JOUR

T1 - RNF43/ZNRF3 negatively regulates taste tissue homeostasis and positively regulates dorsal lingual epithelial tissue homeostasis

AU - Lu, Chanyi

AU - Lin, Xiaoli

AU - Yamashita, Jumpei

AU - Xi, Ranhui

AU - Zhou, Minliang

AU - Zhang, Yali V

AU - Wang, Hong

AU - Margolskee, Robert F

AU - Koo, Bon-Kyoung

AU - Clevers, Hans

AU - Matsumoto, Ichiro

AU - Jiang, Peihua

N1 - Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2022/2/8

Y1 - 2022/2/8

N2 - Taste bud cells are renewed throughout life in a process requiring innervation. Recently, we reported that R-spondin substitutes for neuronal input for taste cell regeneration. R-spondin amplifies WNT signaling by interacting with stem-cell-expressed E3 ubiquitin ligases RNF43/ZNRF3 (negative regulators of WNT signaling) and G-protein-coupled receptors LGR4/5/6 (positive regulators of WNT signaling). Therefore, we hypothesized that RNF43/ZNRF3 may serve as a brake, controlled by gustatory neuron-produced R-spondin, for regulating taste tissue homeostasis. Here, we show that mice deficient for Rnf43/Znrf3 in KRT5-expressing epithelial stem/progenitor cells (RZ dKO) exhibited taste cell hyperplasia; in stark contrast, epithelial tissue on the tongue degenerated. WNT signaling blockade substantially reversed all these effects in RZ dKO mice. Furthermore, innervation becomes dispensable for taste cell renewal in RZ dKO mice. We thus demonstrate important but distinct functions of RNF43/ZNRF3 in regulating taste versus lingual epithelial tissue homeostasis.

AB - Taste bud cells are renewed throughout life in a process requiring innervation. Recently, we reported that R-spondin substitutes for neuronal input for taste cell regeneration. R-spondin amplifies WNT signaling by interacting with stem-cell-expressed E3 ubiquitin ligases RNF43/ZNRF3 (negative regulators of WNT signaling) and G-protein-coupled receptors LGR4/5/6 (positive regulators of WNT signaling). Therefore, we hypothesized that RNF43/ZNRF3 may serve as a brake, controlled by gustatory neuron-produced R-spondin, for regulating taste tissue homeostasis. Here, we show that mice deficient for Rnf43/Znrf3 in KRT5-expressing epithelial stem/progenitor cells (RZ dKO) exhibited taste cell hyperplasia; in stark contrast, epithelial tissue on the tongue degenerated. WNT signaling blockade substantially reversed all these effects in RZ dKO mice. Furthermore, innervation becomes dispensable for taste cell renewal in RZ dKO mice. We thus demonstrate important but distinct functions of RNF43/ZNRF3 in regulating taste versus lingual epithelial tissue homeostasis.

KW - Animals

KW - Benzeneacetamides/pharmacology

KW - Epithelium/metabolism

KW - Glossopharyngeal Nerve/surgery

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Pyridines/pharmacology

KW - Stem Cells/cytology

KW - Taste/physiology

KW - Taste Buds/metabolism

KW - Tongue/cytology

KW - Ubiquitin-Protein Ligases/deficiency

KW - Wnt Signaling Pathway/drug effects

U2 - 10.1016/j.stemcr.2021.12.002

DO - 10.1016/j.stemcr.2021.12.002

M3 - Article

C2 - 34995498

SN - 2213-6711

VL - 17

SP - 369

EP - 383

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 2

ER -