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

Lu, Chanyi; Lin, Xiaojun; Yamashita, Jumpei; Xi, Ranhui; Zhou, Minliang; Zhang, Yali V.; Wang, Hong; Margolskee, Robert F.; Koo, Bon‐Kyoung; Matsumoto, Ichiro; Jiang, Peihua

doi:10.1016/j.stemcr.2021.12.002

Cited by 11 publications

(17 citation statements)

References 35 publications

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“…Taste buds were recognized as onion-like structures with at least three Krt8+ cells (one of which was also positive for Plcβ2 staining). The numbers of taste buds were counted manually as described previously (20). A section in the middle of the circumvallate papilla for each mouse was used for taste bud counting to alleviate potential sampling bias associated with sections at the most anterior and posterior portions of the circumvallate papilla.…”

Section: Taste Bud Counting and Ganglion Neuron Countingmentioning

confidence: 99%

Gustatory-neuron-supplied R-spondin-2 is required for taste bud replenishment

Xu,

de Araujo,

et al. 2024

Preprint

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Taste buds undergo continuous cell turnover throughout life, and taste cell replenishment relies strictly on innervation, a phenomenon first described almost 150 years ago. Recently, we provided evidence that R-spondin 2 (Rspo2) may be the long-sought gustatory neuron-supplied factor that regulates taste stem cell activity, via its interaction with taste stem/progenitor cell-expressed receptor Rnf43/Znrf3. Yet, whether gustatory-neuron-supplied Rspo2 is strictly required for taste tissue maintenance has not been resolved. Here, we set out to determine the necessity of gustatory-neuron-supplied Rspo2 in taste tissue homeostasis using genetic approaches. We used a mouse line that harbors the neomycin-resistance gene (NeoR) in one of the intron regions of theRspo2gene, which results in reduced expression of Rspo2. The number of taste buds is significantly reduced in these mice, compared to wild-type mice, in both anterior and posterior tongue. This phenotypic change was completely reversed by removingNeoRfrom theRspo2gene, thus making it normal. We also combined adeno-associated virus (AAV)-based delivery of Cre recombinase with a mouse line amenable to Cre-based ablation of theRspo2exons encoding the receptor-binding domains. Such deletion of Rspo2 in the nodose-petrosal-jugular ganglion complex led to nearly complete loss of taste buds in the circumvallate papilla. Thus, we demonstrate that Rspo2 is the long-sought gustatory-neuron-supplied factor that acts on taste stem cells to maintain taste tissue homeostasis.SignificanceWe have known for 150 years that innervation is required to induce and maintain cell replacement in taste buds. Until recently, the identity of the inducing factor produced by neurons was unknown. We have shown that R-spondin alone is sufficient to substitute for neuronal input to induce taste bud regeneration. Using a genetic loss-of-function approach, we now demonstrate that gustatory-neuron-expressed Rspo2 is required to maintain taste tissue homeostasis. Altogether, our work reveals that Rspo2 is the long-sought neuron-supplied factor that regulates the activity of taste stem/progenitor cells.

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Section: Taste Bud Counting and Ganglion Neuron Countingmentioning

confidence: 99%

Gustatory-neuron-supplied R-spondin-2 is required for taste bud replenishment

Xu,

de Araujo,

et al. 2024

Preprint

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“…Putative candidate receptors are CD36 and GPR120 (FFAR4), both of which are expressed in human FP ( 147 ). Activating GPR120 in isolated, cultured TRCs by both a synthetic agonist and linoleic acid (LA) leads to increased intracellular calcium and release of GLP-1 into the culture medium ( 148 ). Moreover, Yasumatsu and colleagues ( 149 ) recently provided electrophysiological evidence for transmission of fat signals from GPR120 along the F-type fibers to the mouse chorda tympani branch of CN VII.…”

Section: Tongue Functions: Mechanical and Sensorymentioning

confidence: 99%

“…In turn, the gustatory nerves require taste bud-derived brain-derived neurotrophic factor (BDNF) ( 227 ) to maintain innervation of taste buds in adulthood ( 228 ). Recently Jiang and colleagues ( 148 , 229 ) have shown that the peptide R Spondin can substitute for the neuronal input that signals maintenance of taste buds. Type II bitter and sweet TRCs instruct neurons via the guidance molecules Sema3A and Sema7A ( 174 ) providing some insight into how taste cell specificity and balance in the numbers of the different types of cells is preserved during TRC renewal.…”

Section: Tongue Renewalmentioning

confidence: 99%

“…Applying either the specific synthetic GPR120 agonist TUG891 or linoleic acid-induced a rapid increase in intracellular calcium followed by GLP-1 secretion into the culture medium; they also induced ERK1/2 phosphorylation in HBO cells. Both actions were decreased in HBO cells when calcium homeostasis modulator 1 (CALMH1) was genetically nullified ( 148 ). Interestingly, inhibition of ERK1/2 on the tongue of healthy human volunteers decreased orogustatory sensitivity to linoleic acid ( 346 ).…”

Section: Research In Progressmentioning

confidence: 99%

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Physiology of the tongue with emphasis on taste transduction

Doyle

Premathilake

Yao

et al. 2023

Physiological Reviews

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The tongue is a complex multifunctional organ that interacts and senses both interoceptively and exteroceptively. Although it is easily visible to almost all of us it is relatively understudied and what is in the literature as regards taste mechanisms is often contradictory or is not comprehensively reported. The tongue is both a motor and a sensory organ: motor in that it is required for speech and mastication, and sensory in that it receives information to be relayed to the central nervous system pertaining to the safety and quality of the contents of the oral cavity. Additionally, the tongue and its taste apparatus form part of an innate immune surveillance system. For example, loss or alteration in taste perception can be an early indication of infection as became evident during the present global SARS-CoV-2 pandemic. Here we particularly emphasize the latest updates in the mechanisms of taste perception, taste bud formation and adult taste bud renewal, the presence, and effects of hormones on taste perception, review the understudied lingual immune system with specific reference to SARS-CoV-2, discuss nascent work on tongue microbiome, as well as addressing the effect of systemic disease on tongue structure and function, especially in relation to taste.

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“…In the mouse small intestine, deletion of either Rnf43 or Znrf3 did not induce a discernible phenotype, while the combined deletion of both genes resulted in expansion of the stem cell zone, and eventually adenoma formation (Koo et al, 2012). The essential roles of Rnf43 and Znrf3 in adult stem cell homeostasis were shown for multiple tissues, including the liver, adrenal gland and tongue (Basham et al, 2019; Belenguer et al, 2022; Lu et al, 2022). Of note, while both ligases show redundant expression in certain tissues, such as the intestine, in other tissues homeostasis depends on expression of only one of the two ligases.…”

Section: Introductionmentioning

confidence: 99%

E3 ligases RNF43 and ZNRF3 display differential specificity for endocytosis of Frizzled family members

Bugter,

van Kerkhof,

Janssen

et al. 2023

Preprint

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The transmembrane E3 ligases RNF43 and ZNRF3 perform key tumour suppressor roles by depleting members of the Frizzled (FZD) family, the primary receptors for WNTs, from the cell surface. Mutational inactivation ofRNF43orZNRF3is a frequent event in cancer, which has been linked to FZD stabilisation and a WNT hypersensitive growth state. Strikingly, inactivating mutations in eitherRNF43orZNRF3display a substantial level of tissue specificity across cancer types, thus raising the question to what extent both ligases are functionally redundant. In this study, we investigate the efficacy of RNF43 and ZNRF3 to remove various FZDs from the cell surface. Our results reveal that RNF43 preferentially downregulates FZD1, FZD5 and FZD7, while ZNRF3 displays improved efficacy towards FZD6 and FZD10. Mechanistically, we show that the RNF43 transmembrane domain (TMD) is a key molecular determinant for cell surface removal of FZD5. Moreover, we find that a TMD swap between RNF43 and ZNRF3 is sufficient to re-direct their preference for downregulation of either FZD5 or FZD6. In summary, we uncover that RNF43 and ZNRF3 preferentially downregulate specific FZDs by a mechanism that involves their TMDs. In line with these observations, FZD homologue expression occurs in tissue-specific patterns that correlate with the incidence ofRNF43orZNRF3mutations in cancers arising from those tissues. Consequently, our data point to druggable vulnerabilities of specific FZD receptors inRNF43-orZNRF3-mutant human cancers.

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

Cited by 11 publications

References 35 publications

Gustatory-neuron-supplied R-spondin-2 is required for taste bud replenishment

Gustatory-neuron-supplied R-spondin-2 is required for taste bud replenishment

Physiology of the tongue with emphasis on taste transduction

E3 ligases RNF43 and ZNRF3 display differential specificity for endocytosis of Frizzled family members

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