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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., Identifying regenerative genes in non-mammalian vertebrates A study on zebrafish has genetically screened 254 genes and identified 7 genes implicated in the development and regeneration of hair cells and other tissues. Humans and other mammals cannot regrow hair cells—inner-ear sensory receptors that enable hearing—whereas non-mammalian vertebrates, including zebrafish, can regrow these following injury. Researchers from the United States, led by the National Institutes of Health’s Shawn Burgess, screened adult zebrafish for genes active during the regeneration of inner-ear epithelium. The researchers then produced zebrafish without these genes to study their functions. The studies tested 254 genes known to respond during regeneration, and identified seven specifically impacting regeneration. Most of these seven genes also functioned in liver and fin tissue regeneration. Understanding the mechanisms of these genes may enable future research into regenerative therapies in humans.