eNeuro · 4 authors, 1 centre
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This study identifies the transcription factor Etv1 (Er81) as a key regulator of differentiation for taste cells that detect sweet, umami, and salty (sodium) tastes in mice. Etv1 is expressed in these specific taste cell types and is required for proper expression of taste receptor genes (T1Rs and Scnn1a) and normal nerve responses to these tastes. The findings advance understanding of taste cell turnover and lineage specification, with potential implications for taste disorders.
**Background:** Taste cells are continuously renewed from stem cells throughout life, but the molecular mechanisms governing their differentiation into specific taste types (sweet, umami, bitter, sour, salty) are poorly understood. The transcription factor Skn-1a (Pou2f3) specifies a lineage for sweet, umami, bitter, and sodium taste cells, but how these cells further differentiate is unknown. Etv1 (Er81), an ETS-family transcription factor known to be involved in neuronal differentiation, was identified as enriched in taste buds, prompting investigation into its role in taste cell differentiation.
**Methods:** The authors used wild-type C57BL/6J mice and Etv1^CreERT2/CreERT2 (Etv1^C/C) mice, which carry a CreERT2 insertion disrupting Etv1 in taste cells but express an Etv1 isoform (Etv1-v2) in proprioceptive neurons, allowing viability. Gene expression was analyzed by in situ hybridization and quantitative PCR in taste buds from circumvallate papillae (CvP), fungiform papillae (FuP), and soft palate. Taste cell populations were quantified using tdTomato reporter labeling (Etv1^C/+;R26^Tom/+ and Etv1^C/C;R26^Tom/+ mice) with immunohistochemistry for markers IP3R3 (Skn-1a-dependent cells), Ddc (sour cells), and KCNQ1 (all taste cells). Gustatory neuron integrity was assessed in geniculate ganglia (GG) by in situ hybridization for P2x2 and Etv1. Chorda tympani nerve recordings measured electrophysiological responses to sweet (sucrose, acesulfame K, SC45647), umami (IMP, MSG, MSG+IMP), salty (NaCl with/without amiloride), bitter (denatonium), and sour (citric acid) stimuli in 8 mice per genotype, with experimenters blinded.
**Key Results:** Etv1 mRNA was expressed in a subset of Skn-1a-dependent taste cells in all gustatory areas, specifically in Tas1r3+ cells (sweet/umami) and Scnn1a+ cells (sodium taste), but not in Tas2r+ (bitter) cells. In Etv1^C/C mice, Etv1 mRNA was completely absent from taste buds. Tas1r1 (umami receptor) was completely absent from all gustatory areas. Tas1r2 (sweet receptor) was almost completely lost in CvP and completely lost in FuP and palate. Tas1r3 expression was markedly reduced (weaker and sparser signals; qPCR showed drastic decrease in CvP). Scnn1a co-expression with Skn-1a in sodium taste cells was rarely observed in Etv1^C/C mice, while Scnn1a expression in Pkd2l1+ sour cells was unaltered. Expression of downstream signaling genes (Calhm3, Calhm1, Plcb2) showed significant decreases in some areas, while Gnat3, Trpm5, and bitter/sour markers were largely unchanged. Taste cell population analysis revealed that tdTomato+ (Etv1-lineage) cells were significantly decreased to about half in CvP and palate of Etv1^C/C mice, but total IP3R3+, Ddc+, and KCNQ1+ cell numbers were unaltered. In FuP, tdTomato+ cell numbers were not significantly different. Geniculate ganglion neurons showed comparable Etv1+/P2x2+ ratios and P2x2+ fiber projections between genotypes. Chorda tympani nerve recordings showed significantly reduced responses to sucrose (p<0.0001, genotype effect; significant at 100, 300, 1000 mM), acesulfame K (p=0.0014), SC45647 (p=0.0002), IMP (p<0.0001), MSG (p<0.0001), and MSG+IMP (p<0.0001). NaCl responses were severely reduced with complete loss of amiloride-sensitive components, while amiloride-insensitive components remained almost normal. Bitter (denatonium, p=0.93) and sour (citric acid, p=0.068) responses were unchanged.
**Clinical Implications:** This study identifies Etv1 as a critical transcription factor for the differentiation of sweet, umami, and sodium taste cells, acting downstream of Skn-1a to regulate taste receptor gene expression. These findings advance understanding of taste cell homeostasis and lineage specification, which may inform research into taste disorders, age-related taste loss, and conditions affecting nutritional intake. The Etv1^C/C mouse model, which is viable and lacks taste-specific Etv1 while retaining proprioceptive function, provides a valuable tool for studying taste cell biology and potentially for cancer research given Etv1's roles in prostate cancer, gastrointestinal stromal tumors, and pancreatic cancer.