! Like other areas of the nervous system, the retina is subject to many acquired and inherited neuronal degenerative diseases. Since the retina provides the input for all visual sensory information to the brain, the loss of cells results in visual impairment and potentially complete blindness. Many retinal degenerative diseases affect only a subset of the retinal cells, although, frequently in more advanced disease, loss and reorganization of the entire retina can occur. In mammals, there is very limited regeneration of the degenerated cells; however, in fish, new neurons of all types regenerate from Mller glia (MG) following retinal damage and they are functionally integrated into the existing circuitry. Although mammals, including people, lack this ability, MG, the cellular source for regeneration, are present in all vertebrate retinas. We hypothesize that regeneration from mammalian MG is limited because they fail to express the proneural program of gene expression after injury. We have found that viral over-expression of a proneural transcription factor can partly reprogram mammalian MG to a neurogenic state in vitro. For in vivo confirmation, we generated a transgenic mouse to express Ascl1 in MG. When we induce Ascl1 expression in adult MG, the combination of Ascl1 and histone deacetylase (HDAC) inhibition can stimulate new neuron production from MG in adult mice after NMDA induced damage. The MG-derived neurons primarily resemble bipolar or amacrine cells, and form connections with the existing retinal circuitry. These results show for the first time that functional neurons can be regenerated in an adult mammalian retina and properly integrate within the existing host circuit, but raise a key question: Why do the MG only produce bipolar cells and amacrine cells? In this proposal we outline studies to better understand, and potentially overcome, the barriers to regeneration in mammalian retina. !

Public Health Relevance

! Like other areas of the nervous system, the retina is subject to many acquired and inherited neuronal degenerative diseases. Since regeneration of new retinal neurons does not occur in people, these diseases can leave them with permanent visual impairment. In this proposal we outline experiments to determine the factors that prevent regeneration in the mammalian retina, to obtain information that can be used to promote the regenerative potential of mammalian Mller glia, and lead to novel strategies for treatment of human retinal degeneration. !

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021482-10
Application #
9918884
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Greenwell, Thomas
Project Start
2011-04-01
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Washington
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Jorstad, Nikolas L; Wilken, Matthew S; Grimes, William N et al. (2017) Stimulation of functional neuronal regeneration from Müller glia in adult mice. Nature 548:103-107
Wohl, Stefanie G; Jorstad, Nikolas L; Levine, Edward M et al. (2017) Müller glial microRNAs are required for the maintenance of glial homeostasis and retinal architecture. Nat Commun 8:1603
Wohl, Stefanie G; Reh, Thomas A (2016) The microRNA expression profile of mouse Müller glia in vivo and in vitro. Sci Rep 6:35423
Wilken, Matthew S; Reh, Thomas A (2016) Retinal regeneration in birds and mice. Curr Opin Genet Dev 40:57-64
Wohl, Stefanie Gabriele; Reh, Thomas Andrew (2016) miR-124-9-9* potentiates Ascl1-induced reprogramming of cultured Müller glia. Glia 64:743-62
Reh, Thomas A (2016) Photoreceptor Transplantation in Late Stage Retinal Degeneration. Invest Ophthalmol Vis Sci 57:ORSFg1-7
Ueki, Yumi; Wilken, Matthew S; Cox, Kristen E et al. (2015) A transient wave of BMP signaling in the retina is necessary for Müller glial differentiation. Development 142:533-43
Zhang, Jianmin; Taylor, Russell J; La Torre, Anna et al. (2015) Ezh2 maintains retinal progenitor proliferation, transcriptional integrity, and the timing of late differentiation. Dev Biol 403:128-38
Wilken, Matthew S; Brzezinski, Joseph A; La Torre, Anna et al. (2015) DNase I hypersensitivity analysis of the mouse brain and retina identifies region-specific regulatory elements. Epigenetics Chromatin 8:8
Ueki, Yumi; Wilken, Matthew S; Cox, Kristen E et al. (2015) Transgenic expression of the proneural transcription factor Ascl1 in Müller glia stimulates retinal regeneration in young mice. Proc Natl Acad Sci U S A 112:13717-22

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