Abstract
Degeneration of retinal neurons is an underlying cause of several major types of blinding diseases, and effective therapies remain to be developed. The suppositive strategy of repopulating a degenerative retina with new cells generated onsite faces serious challenges, because the mammalian retina seems to lack the ability to regenerate itself or replace its lost neurons. We investigated the possibility of using a transcriptional factor with proneural activities to reprogram ocular tissue with regenerative capability to give rise to retinal cells. Transgenic mice were generated with DNA constructs that targeted the expression in the retinal pigment epithelium of proneural gene neurogenin1 from the promoter of Bestrophin1, or neurogenin3 from RPE65 promoter. Here we report the presence of ectopic retina-like tissue in some of the transgenic mice, young and aged. The ectopic retina-like tissue contained cells positive for photoreceptor proteins Crx, recoverin, red opsin, and rhodopsin, and cells positive for proteins that label other types of retinal neurons, including AP2α and Pax6 for amacrine cells, Otx2 for bipolar cells, and Brn3A for ganglion cells. The retina-like tissue often co-existed with darkly pigmented tissue positive for RPE proteins: cytokeratin 18, Otx2, and RPE65. The ectopic retina-like tissue was detected in the subretinal space, including two retinae co-existing in the same eye, and/or in the optic nerve or in the vicinity of the optic nerve head. On rare occasions, it was detected in the choroid and in the vicinity of the ciliary body. The presence of ectopic retina-like tissue in the transgenic mouse supports the possibility of inducing retinal regeneration in the mammalian eyes through gene-directed reprograming.
Highlights
The neural retina is a thin tissue in the back of the eye and is responsible to initiate vision when the light enters the eye
To determine whether the PVMD2-ngn1 and PRPE65-ngn3 designs in generating transgenic mice [32] could promote the generation of retina-like tissue, we examined the eyes of the transgenic mice with histology and immunohistology
The underlying theme of the creation of PVMD2-ngn1 and PRPE65-ngn3 transgenic mice [32] was to use the proneural activities of ngn1 and ngn3 to channel retinal pigment epithelium (RPE)’s proliferation and plasticity towards de novo generation of retinal neurons, photoreceptor cells, as observed with cultured RPE cells derived from chick embryos [38]
Summary
The neural retina is a thin tissue in the back of the eye and is responsible to initiate vision when the light enters the eye. Photoreceptor cells capture photons and generate electrophysiological signals. The signals are modulated by interneurons comprised of horizontal, bipolar, and amacrine cells and relayed by retinal ganglion cells to the brain for visual perception. Outside the neural retina lies a single-layered, darkly pigmented, nonneural tissue—the retinal pigment epithelium (RPE), which plays important roles in retinal. Retinal degeneration and RPE atrophy are the main causes of many common forms of visual loss, including retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, and glaucoma. The low quality of life of people with visual loss has spurred research interests in a wide range of potential therapeutic approaches, including retinal regeneration
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