Regenerative medicine holds great promise for both degenerative diseases and traumatic tissue injury which represent significant challenges to the health care system. Hearing loss, which affects hundreds of millions of people worldwide, is caused primarily by a permanent loss of the mechanosensory receptors of the inner ear known as hair cells. This failure to regenerate hair cells after loss is limited to mammals, while all other non-mammalian vertebrates tested were able to completely regenerate these mechanosensory receptors after injury. To understand the mechanism of hair cell regeneration and its association with regeneration of other tissues, we performed a guided mutagenesis screen using zebrafish lateral line hair cells as a screening platform to identify genes that are essential for hair cell regeneration, and further investigated how genes essential for hair cell regeneration were involved in the regeneration of other tissues. We created genetic mutations either by retroviral insertion or CRISPR/Cas9 approaches, and developed a high-throughput screening pipeline for analyzing hair cell development and regeneration. We screened 254 gene mutations and identified 7 genes specifically affecting hair cell regeneration. These hair cell regeneration genes fell into distinct and somewhat surprising functional categories. By examining the regeneration of caudal fin and liver, we found these hair cell regeneration genes often also affected other types of tissue regeneration. Therefore, our results demonstrate guided screening is an effective approach to discover regeneration candidates, and hair cell regeneration is associated with other tissue regeneration.

中文翻译：

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引导性遗传筛选，以鉴定毛细胞和其他组织再生中必不可少的基因。

再生医学对退行性疾病和创伤性组织损伤都具有广阔的前景，这对卫生保健系统构成了重大挑战。听力损失主要影响内耳被称为毛细胞的机械感觉受体的永久性丧失，这种听力损失影响了全球成千上万人。这种丢失后不能再生毛细胞的失败仅限于哺乳动物，而受测的所有其他非哺乳动物脊椎动物在受伤后能够完全再生这些机械感觉受体。为了解毛细胞再生的机制及其与其他组织再生的关系，我们使用斑马鱼侧线毛细胞作为筛选平台进行了诱变诱变筛选，以鉴定对毛细胞再生至关重要的基因，并进一步研究了毛细胞再生必不可少的基因如何参与其他组织的再生。我们通过逆转录病毒插入或CRISPR / Cas9方法创造了基因突变，并开发了高通量筛选管道来分析毛细胞的发育和再生。我们筛选了254个基因突变，并鉴定了7个专门影响毛细胞再生的基因。这些毛细胞再生基因分为不同的且有些令人惊讶的功能类别。通过检查尾鳍和肝脏的再生，我们发现这些毛细胞再生基因经常也影响其他类型的组织再生。因此，我们的结果表明，引导筛查是发现再生候选物的有效方法，并且毛细胞再生与其他组织再生相关。