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

Replenishment of taste cells in taste buds throughout life requires innervation. Recently, we provided evidence that R-spondin is sufficient to promote taste cell generation and restore taste buds in a nerve transection model. Yet, the necessity of gustatory-neuron-supplied R-spondin 2 (RSPO2) in taste tissue homeostasis has remained unresolved. We used genetic approaches to investigate this. In a strain that carries an Rspo2 hypomorphic allele, the number of taste buds was significantly reduced in these mice, compared to wild-type mice, in both anterior and posterior tongue. Specific ablation of Rspo2 in the nodose-petrosal-jugular ganglion complex in another mouse strain led to nearly complete loss of taste buds in the circumvallate papilla. Epithelial ablation of Rnf43/Znrf3, the activity of which is antagonized by R-spondin binding, led to exuberant, sustained expansion of taste buds. Thus, our data strongly support that the RSPO2-RNF43/ZNRF3 axis serves as a master regulator for taste tissue homeostasis.