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Reprogramming of Müller glia cells in mammalian retina promotes regeneration of neuronal cells following injury

A US study, published in the journal Nature (Aug 3rd, 2017), has shown that a regenerative gene from zebrafish is capable of driving the generation of neuronal cells in the mammalian retina. Damaged retina in zebrafish results in cells within the eye regenrating new cells to permit the fish to maintain vision, in contrast to mammalian retina which lack such capability. In experiments in rodents, the engineering of a zebrafish gene into the mouse retina facilitated the development of new cells that appear capable of integrating succesfully into surrounding tissue. The technique suggests a potential mechanism to develop renewable retinal cells in some retinal disorders. If reproducible in humans, the technology may potentially provide a novel strategy for the repair damaged retina.


The research, conduceted by investigators from the University of Washington, Seattle, focused on the Ascl1 gene – a transcription factor – isolated from zebrafish and engineered into mouse retina in such a manner that permitted the researchers to turn the gene on and off by making expression of the gene subject to the addition of a external drug. When the gene was turned on, its activity in damaged retina demonstrated that the cell characteristics of Müller glia changed to interneuron like activity, including pre- and post synaptic development, indicating communication with host circuitry. Within approximately two weeks of an artificial injury, the interneuron cells were shown to respond to light. Additional analyses of the genome structure in test and controls indicated that Müller glia cells had been genetically reprogrammed to exhibit characteristics of interneurons. The activity of the zebrafish Ascl1 gene was further enhanced by the researchers performing a library screen and identifying a commonly used small molecule anti-cancer agent, trichostatin A (TSA). In adult mice, Ascl1 did not appear to work as efficiently as in juvenile animals however, the use of TSA facilitated access for Ascl1 to the required gene locations in the mouse to facilitate regeneration.


According to the researchers, the application of the process may be valuable to treat certain acute eye injuries and central retinal arterial occlusion. Commenting on the achievement, Tom Greenwell, Ph.D., program director at NEI which funded the research, stated: “The findings are significant because they suggest the feasibility of a novel approach for encouraging regeneration in the mammalian retina, the light sensitive tissue at the back of the eye that dies in many blinding diseases. Importantly, the investigation also demonstrates that newly generated cells in the mouse retina not only look and behave like neurons, they also wire correctly to the existing neural circuitry at the back of the eye.”