title: Induction of ectopic retina-like tissue by transgenic expression of neurogenin.
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.
authors: Department of Ophthalmology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America.
authors: Run-Tao
authors: RT
authors: Yan
authors: Department of Ophthalmology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America.
authors: Li
authors: L
authors: He
authors: Department of Ophthalmology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America.
authors: Wenjie
authors: W
authors: Zhan
authors: Department of Ophthalmology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States of America.
authors: Shu-Zhen
authors: SZ
authors: Wang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D063928:Ependymoglial Cells / Q000378:metabolism; D015870:Gene Expression; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009900:Optic Nerve / Q000166:cytology; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology*; D012038:Regeneration
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C486336:Neurog1 protein, mouse
references: Development. 2000 Aug;127(16):3581-91
references: 10903182
references: Mech Dev. 2000 May;93(1-2):59-69
references: 10781940
references: Brain Res Dev Brain Res. 2002 Mar 31;134(1-2):31-41
references: 11947935
references: Am J Pathol. 2002 Oct;161(4):1515-24
references: 12368224
references: Development. 2003 Jul;130(13):2903-15
references: 12756174
references: J Biol Chem. 2003 Jun 13;278(24):21721-31
references: 12663655
references: Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3622-8
references: 12882816
references: Mol Neurobiol. 2003 Oct;28(2):177-94
references: 14576455
references: Dev Biol. 1965 Aug;12(1):79-92
references: 5833111
references: Am J Ophthalmol. 1975 Jul;80(1):1-23
references: 808131
references: Am J Ophthalmol. 1975 Nov;80(5):913-29
references: 811122
references: Invest Ophthalmol Vis Sci. 1981 Jul;21(1 Pt 1):10-6
references: 7251293
references: Dev Biol. 1989 Jul;134(1):201-5
references: 2731647
references: J Neurosci Res. 1993 Mar 1;34(4):414-25
references: 8474143
references: Invest Ophthalmol Vis Sci. 1993 Jul;34(8):2412-24
references: 8325749
references: Invest Ophthalmol Vis Sci. 1995 Feb;36(2):391-405
references: 7531185
references: Science. 1995 Mar 24;267(5205):1788-92
references: 7892602
references: Arch Ophthalmol. 1995 Jul;113(7):939-44
references: 7605288
references: Brain Res. 1995 Apr 24;677(2):300-10
references: 7552256
references: Arch Ophthalmol. 1995 Nov;113(11):1437-46
references: 7487607
references: Curr Eye Res. 1997 Apr;16(4):349-58
references: 9134324
references: Genes Dev. 1999 Mar 15;13(6):649-54
references: 10090721
references: Development. 1999 Oct;126(19):4213-22
references: 10477290
references: Invest Ophthalmol Vis Sci. 2007 Jan;48(1):355-60
references: 17197554
references: Mech Dev. 2008 Jan-Feb;125(1-2):106-16
references: 18042353
references: Graefes Arch Clin Exp Ophthalmol. 2008 Mar;246(3):345-52
references: 17704936
references: Dev Growth Differ. 2008 May;50(4):253-9
references: 18336580
references: Acta Ophthalmol. 2008 Sep;86(6):593-7
references: 18752514
references: Mol Vis. 2008;14:1784-91
references: 18843376
references: Mol Cell Neurosci. 2009 Feb;40(2):187-98
references: 19028584
references: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6685-90
references: 19346468
references: Mol Vis. 2009;15:1000-13
references: 19461929
references: Dev Biol. 2009 Oct 1;334(1):31-45
references: 19596317
references: Invest Ophthalmol Vis Sci. 2009 Dec;50(12):5567-76
references: 19578021
references: J Comp Neurol. 2010 Feb 15;518(4):526-46
references: 20029995
references: Adv Exp Med Biol. 2010;664:211-6
references: 20238019
references: Hum Mol Genet. 2010 May 1;19(9):1791-804
references: 20150232
references: Stem Cells. 2010 Jun;28(6):1048-59
references: 20506130
references: Cell Stem Cell. 2012 Jan 6;10(1):88-95
references: 22226358
references: PLoS Genet. 2012 Jul;8(7):e1002757
references: 22792072
references: Mol Vis. 2013;19:1178-87
references: 23734087
references: Invest Ophthalmol Vis Sci. 2013 Jul;54(7):4766-75
references: 23847312
references: Invest Ophthalmol Vis Sci. 2000 Mar;41(3):903-8
references: 10711712
references: Science. 2000 Mar 17;287(5460):2032-6
references: 10720333
references: Biochem Biophys Res Commun. 2000 Apr 13;270(2):517-21
references: 10753656
references: Dev Dyn. 2001 Jul;221(3):342-9
references: 11458394