Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
Cell Rep. 2019 Aug 20;28(8):2037-2047.e4. doi: 10.1016/j.celrep.2019.07.061.
Unlike the adult mammalian retina, Müller glia (MG) in the adult zebrafish retina are able to dedifferentiate into a "stem cell"-like state and give rise to multipotent progenitor cells upon retinal damage. We show that miR-216a is downregulated in MG after constant intense light lesioning and that miR-216a suppression is necessary and sufficient for MG dedifferentiation and proliferation during retina regeneration. miR-216a targets the H3K79 methyltransferase Dot1l, which is upregulated in proliferating MG after retinal damage. Loss-of-function experiments show that Dot1l is necessary for MG reprogramming and mediates MG proliferation downstream of miR-216a. We further demonstrate that miR-216a and Dot1l regulate MG-mediated retina regeneration through canonical Wnt signaling. This article reports a regulatory mechanism upstream of Wnt signaling during retina regeneration and provides potential targets for enhancing regeneration in the adult mammalian retina.
与成年哺乳动物视网膜不同，成年斑马鱼视网膜中的 Müller 胶质细胞（MG）能够去分化为一种“干细胞样”状态，并在视网膜损伤后产生多能祖细胞。我们发现，miR-216a 在持续强光损伤后在 MG 中下调，miR-216a 的抑制对于 MG 在视网膜再生过程中的去分化和增殖是必要和充分的。miR-216a 靶向 H3K79 甲基转移酶 Dot1l，后者在视网膜损伤后增殖的 MG 中上调。功能丧失实验表明，Dot1l 对于 MG 的重编程是必需的，并介导 miR-216a 下游的 MG 增殖。我们进一步证明，miR-216a 和 Dot1l 通过经典 Wnt 信号通路调节 MG 介导的视网膜再生。本文报道了视网膜再生过程中 Wnt 信号的上游调控机制，并为增强成年哺乳动物视网膜的再生提供了潜在的靶点。
