PNAS：Wnt途径可促进听觉祖细胞发育

<div id="region-column1and2-layout2">内耳毛细胞是听觉感受系统中必不可少的成员，毛细胞的缺失或损伤会造成听力障碍，在哺乳动物，毛细胞被认为是不可再生的，而在非哺乳的脊椎动物中，比如鸟类和两栖动物，支持细胞能促进毛细胞的再生。</div>
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以前的研究表明，虽然感觉上皮是没有分裂能力的组织，但其中有一部分细胞通过体外培养可以像听觉祖细胞一样分化为毛细胞。Lgr5（Leucine-rich repeat-containing G-protein coupled receptor 5）是Wnt途径的一个靶基因，特异表达在新生儿的耳蜗支持细胞。

本文的研究者首先对于Lgr5阳性的细胞是Wnt敏感的听觉前体细胞这一假说进行了验证。通过流式分选，研究人员得到了初生小鼠的Lgr5阳性细胞，这些细胞在体外培养中能够形成像听觉祖细胞一样的集落。经过10天的分化过程，这些细胞形成了新的听觉细胞，并且表现出毛细胞特有的分子标记(myo7a, calretinin, parvalbumin, myo6)和纤毛状结构。通过激活Wnt途径，可以促进Lgr5阳性克隆的增殖。而如果抑制Wnt途径，Lgr5阳性细胞的增殖则会减少。此外，研究人员还发现，过表达β-catenin 可以促进耳蜗感觉上皮中Lgr5阳性细胞的增殖。本研究的结果证明了Lgr5是听觉前体细胞的分子标记，而Wnt途径对这群细胞的增殖有促进作用，这为我们研究Wnt信号通路在听觉器官发育中的作用机制提供了新的认识。 
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<a title="" href="http://dx.doi.org/10.1073/pnas.1202774109" target="_blank">doi:10.1073/pnas.1202774109</a>

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<br/><strong>Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea</strong><br/>


Renjie Chaia, Bryan Kuob, Tian Wanga, Eric J. Liawa, Anping Xiaa, Taha A. Jana,c, Zhiyong Liub, Makoto M. Taketod, John S. Oghalaia, Roeland Nussec, Jian Zuob, and Alan G. Chenga

Inner ear hair cells are specialized sensory cells essential for auditory function. Previous studies have shown that the sensory epithelium is postmitotic, but it harbors cells that can behave as progenitor cells in vitro, including the ability to form new hair cells. <em>Lgr5</em>, a Wnt target gene, marks distinct supporting cell types in the neonatal cochlea. Here, we tested the hypothesis that Lgr5⁺ cells are Wnt-responsive sensory precursor cells. In contrast to their quiescent in vivo behavior, Lgr5⁺ cells isolated by flow cytometry from neonatal <em>Lgr5^{EGFP-CreERT2/+}</em> mice proliferated and formed clonal colonies. After 10 d in culture, new sensory cells formed and displayed specific hair cell markers (myo7a, calretinin, parvalbumin, myo6) and stereocilia-like structures expressing F-actin and espin. In comparison with other supporting cells, Lgr5⁺ cells were enriched precursors to myo7a⁺ cells, most of which formed without mitotic division. Treatment with Wnt agonists increased proliferation and colony-formation capacity. Conversely, small-molecule inhibitors of Wnt signaling suppressed proliferation without compromising the myo7a⁺ cells formed by direct differentiation. In vivo lineage tracing supported the idea that Lgr5⁺ cells give rise to myo7a⁺ hair cells in the neonatal <em>Lgr5^{EGFP-CreERT2/+}</em> cochlea. In addition, overexpression of β-catenin initiated proliferation and led to transient expansion of Lgr5⁺ cells within the cochlear sensory epithelium. These results suggest that Lgr5 marks sensory precursors and that Wnt signaling can promote their proliferation and provide mechanistic insights into Wnt-responsive progenitor cells during sensory organ development.
<div> <br/>来源：生物谷</div>
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