Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration
Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration
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DOI：
10.1073/pnas.1719109115
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发表时间：
2018-01-09
影响因子：
11.1
通讯作者：
Beachy, Philip A.
中科院分区：
文献类型：
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作者：
Lu, Wan-Jin;Mann, Randall K.;Beachy, Philip A.
器官在正常组织更新或损伤后如何保持和恢复功能完整性是一个中心生物学问题。140年前，人们发现舌头味觉器官的维持依赖于远处神经节神经元的神经支配，但其潜在机制仍不清楚。在这里，我们表明，编码分泌蛋白信号的Sonic hedgehog（Shh）在这些感觉神经元中表达，并且神经元Shh表达的实验性消融导致味觉受体细胞（TRC）的损失。TRC也在hedgehog途径反应的药理学阻断后丢失，这是经历hedgehog抑制剂治疗的癌症患者所经历的味觉丧失的原因。我们发现，TRC再生后，这样的药理学消融需要神经元表达的Shh，并可以大大增强刺猬反应的药理学激活。然而，这种刺猬反应的药理学增强导致在许多异位部位形成额外的TRC，这与Sbb表达神经元的投射模式所指定的部位限制性再生不同。因此，TRC的稳定再生需要神经元Shh，这说明了神经元传递诸如Shh信号的线索可以使远端细胞反应模式化以确保组织维持和再生期间的功能完整性的原理。
How organs maintain and restore functional integrity during ordinary tissue turnover or following injury represents a central biological problem. The maintenance of taste sensory organs in the tongue was shown 140 years ago to depend on innervation from distant ganglion neurons, but the underlying mechanism has remained unknown. Here, we show that Sonic hedgehog (Shh), which encodes a secreted protein signal, is expressed in these sensory neurons, and that experimental ablation of neuronal Shh expression causes loss of taste receptor cells (TRCs). TRCs are also lost upon pharmacologic blockade of hedgehog pathway response, accounting for the loss of taste sensation experienced by cancer patients undergoing hedgehog inhibitor treatment. We find that TRC regeneration following such pharmacologic ablation requires neuronal expression of Shh and can be substantially enhanced by pharmacologic activation of hedgehog response. Such pharmacologic enhancement of hedgehog response, however, results in additional TRC formation at many ectopic sites, unlike the site-restricted regeneration specified by the projection pattern of Sbb-expressing neurons. Stable regeneration of TRCs thus requires neuronal Shh, illustrating the principle that neuronal delivery of cues such as the Shh signal can pattern distant cellular responses to assure functional integrity during tissue maintenance and regeneration.