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 Shh-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.
epression is a leading cause of disability worldwide, interfering with daily activities, quality of life, and function, and sometimes leading to self-harm and suicide. In 2017 alone, more than 264 million people had major depressive disorder worldwide. 1 Major depressive disorder is a result of complicated interactions between psychosocial, genetic, and environmental factors that combine to produce a common constellation of symptoms that include sad or depressed mood, loss of interest, increased fatigue, feelings of guilt, and thoughts of suicide. 2 Many effective treatments for major depressive disorder exist, including psychotherapy and antidepressant medications such as selective-serotonin reuptake inhibitors and tricyclic antidepressants. Despite rapid growth in the number of available treatments for major depressive disorder over the past
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