Her6 and Prox1a are novel regulators of photoreceptor regeneration in the zebrafish retina.

Damage to light-sensing photoreceptors (PRs) occurs in highly prevalent retinal diseases. As humans cannot regenerate new PRs, these diseases often lead to irreversible blindness. Intriguingly, animals, such as the zebrafish, can regenerate PRs efficiently and restore functional vision. Upon injury, mature Müller glia (MG) undergo reprogramming to adopt a stem cell-like state. This process is similar to cellular dedifferentiation, and results in the generation of progenitor cells, which, in turn, proliferate and differentiate to replace lost retinal neurons. In this study, we tested whether factors involved in dedifferentiation of Drosophila CNS are implicated in the regenerative response in the zebrafish retina. We found that hairy-related 6 (her6) negatively regulates of PR production by regulating the rate of cell divisions in the MG-derived progenitors. prospero homeobox 1a (prox1a) is expressed in differentiated PRs and may promote PR differentiation through phase separation. Interestingly, upon Her6 downregulation, Prox1a is precociously upregulated in the PRs, to promote PR differentiation; conversely, loss of Prox1a also induces a downregulation of Her6. Together, we identified two novel candidates of PR regeneration that cross regulate each other; these may be exploited to promote human retinal regeneration and vision recovery. Author summary: Nerve cells in the central nervous system of humans and other mammals do not regenerate after damage (e.g. brain injury or genetic degenerative disorders). Damage to the visual neurons for instance often results in complete and irreversible blindness. Here, we used the regenerative zebrafish model to investigate novel genes regulating this response. We identify two genes that are expressed at separate times following injury, specifically in the regenerative stem cells of the visual system. By disrupting the expression of these, we showed novel important roles in controlling stem cell divisions (required to make more cells) and in nerve cell maturation (required to regenerate the fully functioning nerve cells). Both are ancient genes present in many evolutionary distant animals and were identified in our study by their ability to affect stem cells in the fruit fly brain. [ABSTRACT FROM AUTHOR]

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