Unlike mammals, zebrafish are able to regenerate a damaged retina and restore lost sight. This regenerative ability depends on Muller glia (MG) that respond to retinal injury by undergoing multiple shifts in identity as they dedifferentiate, proliferate, and finally differentiate to regenerate new neurons and glia. Although MG can be coaxed to proliferate in the injured mammalian retina, they do not exhibit multipotency and only rarely regenerate damaged neurons. Therefore understanding the mechanisms driving zebrafish MG reprogramming to mutlipotency may suggest novel strategies for generating multipotent progenitors from mammalian MG. Recent studies suggest that MG reprogramming is accompanied by activation of gene expression programs that are similar to those acting in embryonic stem cells and retinal progenitors. We hypothesize that genetic programs driving MG dedifferentiation and multipotency are controlled by DNA methylation. In animals, DNA methylation predominantly occurs at CpG dinucleotides and controls transcriptional regulatory processes like imprinting, X-chromosome inactivation, transposon silencing, and stable silencing of gene activity. Methylation of DNA proximal to gene-coding regions is correlated with gene silencing. Importantly, changes in DNA methylation have been correlated with the activation and suppression of gene expression programs that take place during early development and accompany the reprogramming of somatic cells to yield induced pluripotent stem cells. It is likely that erasure and reestablishment of genomic methylation, at key locations, accompanies the gene expression changes that drive MG dedifferentiation and multipotency and subsequently the regeneration of new retinal cell types. Here we propose to identify regions of the MG genome that are undergoing methylation changes during retina regeneration and determine if these changes correlate with gene expression changes that have previously been characterized using microarray technology. In addition, we propose to test the hypothesis that DNA demethylation in dedifferentiating MG is an active process driven by Apobec2a and 2b proteins.

Public Health Relevance

Damage or disease of the mammalian retina often leads to irreparable blindness. In contrast, zebrafish are able to regenerate a damaged retina and regain lost sight. Key to successful regeneration in zebrafish is Muller glia that responds to retinal injry by dedifferentiating and generating a population of proliferating multipotent retinal progenitors. Understanding the mechanisms underlying Muller glia dedifferentiation and acquisition of multipotentiality in zebrafish may suggest novel strategies for stimulating Muller glia dedifferentiation and retinal repair in humans suffering from blinding eye diseases and injuries.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (BVS)
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Greenwell, Thomas
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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