Inhibition of Notch activity promotes nonmitotic regeneration of hair cells in the adult mouse utricles.
Inhibition of Notch activity promotes nonmitotic regeneration of hair cells in the adult mouse utricles.
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DOI：
10.1523/jneurosci.2057-11.2011
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发表时间：
2011-10-26
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影响因子：
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通讯作者：
Stone JS
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文献类型：
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作者：
Lin V;Golub JS;Nguyen TB;Hume CR;Oesterle EC;Stone JS
成年哺乳动物再生感觉毛细胞的能力尚未明确界定。为了探究这一过程的早期阶段，我们在培养条件下用新霉素诱导毛细胞死亡后，检测了成年小鼠椭圆囊中一个瞬时表达的发育基因Atoh1的重新激活情况。利用针对Atoh1增强子的腺病毒报告基因，我们发现新霉素处理3天后，Atoh1转录在一些毛细胞前体细胞（支持细胞）中被激活。到新霉素处理后18天，具有Atoh1转录活性的细胞数量显著增加，但很少有细胞获得毛细胞特征（即积累ATOH1或肌球蛋白VIIa蛋白或形成静纤毛）。用γ-分泌酶抑制剂DAPT处理，可降低Notch通路活性，增强Atoh1转录活性，并显著增加具有毛细胞特征的Atoh1表达细胞的数量，但仅在椭圆囊斑/近椭圆囊斑区域。用另一种Notch活性所需酶（TACE）的抑制剂TAPI - 1也观察到了类似的效果。在任何对照组或DAPT处理的椭圆囊中，支持细胞的分裂都很少见。这项研究表明，成年哺乳动物具有启动前庭毛细胞再生的天然能力，并提示区域Notch活性是损伤后支持细胞直接转分化为毛细胞的重要抑制因素。
The capacity of adult mammals to regenerate sensory hair cells is not well defined. To explore early steps in this process, we examined reactivation of a transiently expressed developmental gene, Atoh1, in adult mouse utricles after neomycin-induced hair cell death in culture. Using an adenoviral reporter for Atoh1 enhancer, we found that Atoh1 transcription is activated in some hair cell progenitors (supporting cells) three days after neomycin treatment. By 18 days post-neomycin, the number of cells with Atoh1 transcriptional activity increased significantly, but few cells acquired hair cell features (i.e., accumulated ATOH1 or myosin VIIa protein or developed stereocilia). Treatment with DAPT, an inhibitor of γ-secretase, reduced notch pathway activity, enhanced Atoh1 transcriptional activity, and dramatically increased the number of Atoh1-expressing cells with hair cell features, but only in the striolar/juxtastriolar region. Similar effects were seen with TAPI-1, an inhibitor of another enzyme required for notch activity (TACE). Division of supporting cells was rare in any control or DAPT-treated utricles. This study shows that mature mammals have a natural capacity to initiate vestibular hair cell regeneration and suggests that regional notch activity is a significant inhibitor of direct transdifferentiation of supporting cells into hair cells following damage.