Notch Suppression Collaborates with Ascl1 and Lin28 to Unleash a Regenerative Response in Fish Retina, But Not in Mice
Notch Suppression Collaborates with Ascl1 and Lin28 to Unleash a Regenerative Response in Fish Retina, But Not in Mice
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DOI：
10.1523/jneurosci.2126-17.2018
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发表时间：
2018-02-28
影响因子：
5.3
通讯作者：
Goldman, Daniel
中科院分区：
文献类型：
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作者：
Elsaeidi, Fairouz;Macpherson, Peter;Goldman, Daniel
斑马鱼视网膜Muller胶质（MG）细胞通过获得视网膜干细胞特征对损伤作出反应。成千上万的基因表达变化与这一事件有关。这些变化的关键是Ascl1a和Lin28a的诱导，这两个重编程因子的表达是视网膜再生所必需的。这些因素是否足以驱动MG增殖和随后的神经元命运规范仍不清楚。为了验证这一点，我们在雄性和雌性鱼的未损伤视网膜中有条件地表达Ascl1a和Lin28a。我们发现，它们的强制表达只刺激稀疏的MG增殖。然而，结合Notch信号抑制，广泛的MG增殖和神经元再生随之而来。值得注意的是，雄性和雌性小鼠视网膜中的Ascl1和Lin28a表达也刺激了稀疏的MG增殖，尽管与Notch信号抑制剂联合使用时，这种增殖没有增强。鱼类和小鼠的谱系追踪表明，增殖的MG产生了多能祖细胞；然而，这个过程在鱼身上比在老鼠身上更有效。总之，我们的研究表明，斑马鱼中Ascl1a和Lin28a的过表达，结合Notch信号的抑制，可以在Muller胶质细胞中表型化视网膜损伤的影响。有趣的是，Ascl1和Lin28a似乎在鱼和小鼠中有相似的作用，而Notch信号可能不同。了解Notch信号抑制在鱼类和小鼠中的不同结果，可能为促进哺乳动物视网膜再生提供额外的策略。
Muller glial (MG) cells in the zebrafish retina respond to injury by acquiring retinal stem-cell characteristics. Thousands of gene expression changes are associated with this event. Key among these changes is the induction of Ascl1a and Lin28a, two reprogramming factors whose expression is necessary for retina regeneration. Whether these factors are sufficient to drive MG proliferation and subsequent neuronal-fate specification remains unknown. To test this, we conditionally expressed Ascl1a and Lin28a in the uninjured retina of male and female fish. We found that together, their forced expression only stimulates sparse MG proliferation. However, in combination with Notch signaling inhibition, widespread MG proliferation and neuron regeneration ensued. Remarkably, Ascl1 and Lin28a expression in the retina of male and female mice also stimulated sparse MG proliferation, although this was not enhanced when combined with inhibitors of Notch signaling. Lineage tracing in both fish and mice suggested that the proliferating MG generated multipotent progenitors; however, this process was much more efficient in fish than mice. Overall, our studies suggest that the overexpression of Ascl1a and Lin28a in zebrafish, in combination with inhibition of Notch signaling, can phenocopy the effects of retinal injury in Muller glia. Interestingly, Ascl1 and Lin28a seem to have similar effects in fish and mice, whereas Notch signaling may differ. Understanding the different consequences of Notch signaling inhibition in fish and mice, may suggest additional strategies for enhancing retina regeneration in mammals.