期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 36, 页码 9479-9489出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2447-15.2016
关键词
apoptosis; hair cell; necrosis; regeneration; Wnt
资金
- National Natural Science Foundation of China [81300821]
- Science and Technology Commission of Shanghai Municipality Grant [14DZ2260300]
- Hearing Restoration Project of the Hearing Health Foundation
- NIH NIDCD Grants [R01 007174, P30 DC05209, R03 DC010270]
- Shulsky Foundation
Cochlear hair cells (HCs), the sensory cells that respond to sound, do not regenerate after damage in adult mammals, and their loss is a major cause of deafness. Here we show that HC regeneration in newborn mouse ears occurred spontaneously when the original cells were ablated by treatment with diphtheria toxin (DT) in ears that had been engineered to overexpress the DT receptor, but was not detectable when HCs were ablated in vivo by the aminoglycoside antibiotic neomycin. A variety of Wnts (Wnt1, Wnt2, Wnt2b, Wnt4, Wnt5a, Wnt7b, Wnt9a, Wnt9b, and Wnt11) and Wnt pathway component Krm2 were upregulated after DT damage. Nuclear beta-catenin was upregulated in HCs and supporting cells of the DT-damaged cochlea. Pharmacological inhibition of Wnt decreased spontaneous regeneration, confirming a role of Wnt signaling in HC regeneration. Inhibition of Notch signaling further potentiated supporting cell proliferation and HC differentiation that occurred spontaneously. The absence of new HCs in the neomycin ears was correlated to less robust Wnt pathway activation, but the ears subjected to neomycin treatment nonetheless showed increased cell division and HC differentiation after subsequent forced upregulation of beta-catenin. These studies suggest, first, that Wnt signaling plays a key role in regeneration, and, second, that the outcome of a regenerative response to damage in the newborn cochlea is determined by reaching a threshold level of Wnt signaling rather than its complete absence or presence.
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