Department of Cell and Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Rocky Mountain Taste and Smell Center, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Development. 2018 Jul 17;145(14):dev164889. doi: 10.1242/dev.164889.
Adult tongue epithelium is continuously renewed from epithelial progenitor cells, a process that requires hedgehog (HH) signaling. In mice, pharmacological inhibition of the HH pathway causes taste bud loss within a few weeks. Previously, we demonstrated that sonic hedgehog (SHH) overexpression in lingual progenitors induces ectopic taste buds with locally increased SOX2 expression, suggesting that taste bud differentiation depends on SOX2 downstream of HH. To test this, we inhibited HH signaling in mice and observed a rapid decline in and SOX2-GFP expression in taste epithelium. Upon conditional deletion of , differentiation of both taste and non-taste epithelial cells was blocked, and progenitor cell number increased. In contrast to basally restricted proliferation in controls, dividing cells were overabundant and spread to suprabasal epithelial layers in mutants. SOX2 loss in progenitors also led non-cell-autonomously to taste cell apoptosis, dramatically shortening taste cell lifespans. Finally, in tongues with conditional deletion and SHH overexpression, ectopic and endogenous taste buds were not detectable; instead, progenitor hyperproliferation expanded throughout the lingual epithelium. In summary, we show that SOX2 functions downstream of HH signaling to regulate lingual epithelium homeostasis.
成人舌上皮细胞不断地由上皮祖细胞更新，这一过程需要 hedgehog (HH) 信号。在小鼠中，HH 通路的药理学抑制会在几周内导致味蕾丧失。此前，我们证明了舌祖细胞中 sonic hedgehog (SHH) 的过表达会诱导局部 SOX2 表达增加的异位味蕾，表明味觉细胞分化依赖于 HH 下游的 SOX2。为了验证这一点，我们抑制了小鼠的 HH 信号，观察到味觉上皮中 和 SOX2-GFP 表达迅速下降。在条件性删除 后，味觉和非味觉上皮细胞的分化都被阻断，祖细胞数量增加。与对照组中基底受限增殖相反，分裂细胞过多，并扩散到突变体的上皮上层。祖细胞中 SOX2 的缺失也导致非细胞自主的味觉细胞凋亡，显著缩短了味觉细胞的寿命。最后，在具有条件性 缺失和 SHH 过表达的舌头上，异位和内源性味蕾无法检测到；相反，祖细胞的过度增殖扩展到整个舌上皮。总之，我们表明 SOX2 作为 HH 信号的下游分子，调节舌上皮的稳态。
