Yap-lin28a axis targets let7-Wnt pathway to restore progenitors for initiating regeneration
Yap-lin28a axis targets let7-Wnt pathway to restore progenitors for initiating regeneration
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Yap-lin28a 轴靶向 let7-Wnt 通路以恢复祖细胞以启动再生
DOI：
10.7554/elife.55771
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发表时间：
2020-04-30
期刊：
影响因子：
7.7
通讯作者：
Jiang, Linjia
中科院分区：
文献类型：
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作者：
Ye, Zhian;Su, Zhongwu;Jiang, Linjia
成年哺乳动物内耳中表达sox2的（sox2+）祖细胞失去再生能力，而斑马鱼侧线中的祖细胞能够在整个生命周期中增殖和再生受损的HC。为了模拟哺乳动物的HC损伤，我们建立了一个斑马鱼严重损伤模型，以消除祖细胞和HC。atoh1a表达（atoh1a+）HC前体是严重损伤后存活的主要群体，并获得sox 2表达以启动祖细胞再生。在严重损伤后，雅普被激活上调lin 28 a转录。严重损伤诱导的祖细胞再生在lin 28 a或雅普突变体中失效。相反，lin28a的过表达启动了sox 2+祖细胞的恢复。在机制上，microRNA let7作用于lin28a下游，激活Wnt通路以促进再生。我们的发现，lin28a是必要的和足够的再生耗尽的sox 2+祖细胞揭示恢复祖细胞启动HC再生在哺乳动物。
The sox2 expressing (sox2+) progenitors in adult mammalian inner ear lose the capacity to regenerate while progenitors in the zebrafish lateral line are able to proliferate and regenerate damaged HCs throughout lifetime. To mimic the HC damage in mammals, we have established a zebrafish severe injury model to eliminate both progenitors and HCs. The atoh1a expressing (atoh1a+) HC precursors were the main population that survived post severe injury, and gained sox2 expression to initiate progenitor regeneration. In response to severe injury, yap was activated to upregulate lin28a transcription. Severe-injury-induced progenitor regeneration was disabled in lin28a or yap mutants. In contrary, overexpression of lin28a initiated the recovery of sox2+ progenitors. Mechanistically, microRNA let7 acted downstream of lin28a to activate Wnt pathway for promoting regeneration. Our findings that lin28a is necessary and sufficient to regenerate the exhausted sox2+ progenitors shed light on restoration of progenitors to initiate HC regeneration in mammals.