title: Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice.
abstract: Norrie disease is an X-linked retinal dysplasia that presents with congenital blindness, sensorineural deafness, and mental retardation. Norrin, the protein product of the Norrie disease gene (NDP), is a secreted protein of unknown biochemical function. Norrie disease (Ndp(y/-)) mutant mice that are deficient in norrin develop blindness, show a distinct failure in retinal angiogenesis, and completely lack the deep capillary layers of the retina. We show here that the transgenic expression of ectopic norrin under control of a lens-specific promoter restores the formation of a normal retinal vascular network in Ndp(y/-) mutant mice. The improvement in structure correlates with restoration of neuronal function in the retina. In addition, lenses of transgenic mice with ectopic expression of norrin show significantly more capillaries in the hyaloid vasculature that surrounds the lens during development. In vitro, lenses of transgenic mice in coculture with microvascular endothelial cells induce proliferation of the cells. Transgenic mice with ectopic expression of norrin show more bromodeoxyuridine-labeled retinal progenitor cells at embryonic day 14.5 and thicker retinas at postnatal life than wild-type littermates, indicating a putative direct neurotrophic effect of norrin. These data provide direct evidence that norrin induces growth of ocular capillaries and that pharmacologic modulation of norrin might be used for treatment of the vascular abnormalities associated with Norrie disease or other vascular disorders of the retina.
authors.affiliation: Department of Anatomy, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ohlmann
authors.forename: Michael
authors.initials: M
authors.lastname: Scholz
authors.forename: Andreas
authors.initials: A
authors.lastname: Goldwich
authors.forename: Bharesh K
authors.initials: BK
authors.lastname: Chauhan
authors.forename: Kristiane
authors.initials: K
authors.lastname: Hudl
authors.forename: Anne V
authors.initials: AV
authors.lastname: Ohlmann
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
authors.forename: Ales
authors.initials: A
authors.lastname: Cvekl
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Tamm
mesh_terms: D000818:Animals; D002196:Capillaries / Q000166:cytology / Q000254:growth & development; D002452:Cell Count; D002455:Cell Division; D002478:Cells, Cultured; D002645:Chickens; D018920:Coculture Techniques; D004596:Electroretinography; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007908:Lens, Crystalline / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012160:Retina / Q000503:physiopathology / Q000648:ultrastructure; D012165:Retinal Ganglion Cells / Q000473:pathology; D012171:Retinal Vessels / Q000254:growth & development*; D012867:Skin / Q000098:blood supply; D038204:beta-Crystallins / Q000235:genetics
chemical_list: D005136:Eye Proteins; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D038204:beta-Crystallins
references.citation: Anat Embryol (Berl). 1999 Oct;200(4):403-11
references.pmid: 10460477
references.citation: Dev Biol. 2000 Jul 15;223(2):383-98
references.pmid: 10882523
references.citation: J Neurosci. 2000 Sep 15;20(18):6781-8
references.pmid: 10995821
references.citation: FASEB J. 2001 May;15(7):1215-7
references.pmid: 11344092
references.citation: J Neurosci. 2001 Jul 1;21(13):4761-71
references.pmid: 11425903
references.citation: Nat Genet. 2001 Sep;29(1):70-4
references.pmid: 11528395
references.citation: Prog Retin Eye Res. 2001 Nov;20(6):799-821
references.pmid: 11587918
references.citation: Invest Ophthalmol Vis Sci. 2002 Feb;43(2):522-7
references.pmid: 11818400
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6222-7
references.pmid: 11983912
references.citation: J Neurosci. 2002 Jun 1;22(11):4286-92
references.pmid: 12040033
references.citation: Nat Genet. 2002 Oct;32(2):326-30
references.pmid: 12172548
references.citation: Prog Retin Eye Res. 2002 Sep;21(5):429-47
references.pmid: 12207944
references.citation: Dev Dyn. 2002 Oct;225(2):111-25
references.pmid: 12242711
references.citation: Invest Ophthalmol Vis Sci. 2003 Feb;44(2):839-47
references.pmid: 12556420
references.citation: Brain Res Dev Brain Res. 2003 Feb 16;140(2):169-83
references.pmid: 12586423
references.citation: Am J Physiol Heart Circ Physiol. 2003 Nov;285(5):H1917-38
references.pmid: 12842817
references.citation: Nat Genet. 1992 Oct;2(2):139-43
references.pmid: 1303264
references.citation: Hum Mol Genet. 1992 Oct;1(7):461-5
references.pmid: 1307245
references.citation: Cell. 2004 Mar 19;116(6):883-95
references.pmid: 15035989
references.citation: Exp Eye Res. 2004 Apr;78(4):837-48
references.pmid: 15037118
references.citation: Invest Ophthalmol Vis Sci. 2004 Jul;45(7):2384-90
references.pmid: 15223821
references.citation: J Histochem Cytochem. 1985 Jul;33(7):711-4
references.pmid: 2409130
references.citation: Anal Biochem. 1987 Nov 1;166(2):368-79
references.pmid: 2449095
references.citation: Microvasc Res. 1988 Nov;36(3):275-90
references.pmid: 2466191
references.citation: Invest Ophthalmol. 1972 Aug;11(8):691-8
references.pmid: 5044721
references.citation: J Comp Neurol. 1984 Nov 1;229(3):362-73
references.pmid: 6501608
references.citation: J Neurosci. 1995 Jul;15(7 Pt 1):4738-47
references.pmid: 7623107
references.citation: Biochim Biophys Acta. 1995 Mar 14;1261(1):68-76
references.pmid: 7893762
references.citation: Nat Genet. 1993 Dec;5(4):376-80
references.pmid: 8298646
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):589-95
references.pmid: 8570600
references.citation: Hum Mol Genet. 1996 Jan;5(1):51-9
references.pmid: 8789439
references.citation: Mech Dev. 1996 Jun;57(1):79-89
references.pmid: 8817455
references.citation: Invest Ophthalmol Vis Sci. 1997 Mar;38(3):710-8
references.pmid: 9071226
references.citation: Science. 1997 Jul 11;277(5323):242-5
references.pmid: 9211853
references.citation: Am J Pathol. 1997 Jul;151(1):281-91
references.pmid: 9212753
references.citation: J Biol Chem. 1997 Dec 26;272(52):33410-5
references.pmid: 9407136
references.citation: Invest Ophthalmol Vis Sci. 1998 Jan;39(1):180-8
references.pmid: 9430560
references.citation: Invest Ophthalmol Vis Sci. 1998 Nov;39(12):2450-7
references.pmid: 9804153
references.citation: Acta Anat (Basel). 1998;162(2-3):95-100
references.pmid: 9831755
references.citation: FASEB J. 1999 Jan;13(1):9-22
references.pmid: 9872925