Mutations in Zebrafish Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma

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The glaucomas comprise a genetically complex group of retinal neuropathies that typically occur late in life and are characterized by progressive pathology of the optic nerve head and degeneration of retinal ganglion cells. In addition to age and family history, other significant risk factors for glaucoma include elevated intraocular pressure (IOP) and myopia. The complexity of glaucoma has made it difficult to model in animals, but also challenging to identify responsible genes. We have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adult onset severe myopia, elevated IOP, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a non-complementing allele indicated that non-sense mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. Lrp2, previously named Megalin, functions as an endocytic receptor for a wide-variety of bioactive molecules including Sonic hedgehog, Bone morphogenic protein 4, retinol-binding protein, vitamin D-binding protein, and apolipoprotein E, among others. Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals—but not all—develop high IOP and severe myopia with obviously enlarged eye globes. This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis. Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease.

Vyšlo v časopise: Mutations in Zebrafish Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma. PLoS Genet 7(2): e32767. doi:10.1371/journal.pgen.1001310
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001310

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1. GehrsKM

JacksonJR

BrownEN

AllikmetsR

HagemanGS

2010 Complement, age-related macular degeneration and a vision of the future. Arch Ophthalmol 128 349 358

2. BloomRI

FriedmanIB

ChuckRS

2010 Increasing rates of myopia: the long view. Curr Opin Ophthalmol 21 247 248

3. YoungTL

2009 Molecular genetics of human myopia: an update. Optom Vis Sci 86 E8 E22

4. Loyo-BerriosNI

BlusteinJN

2007 Primary-open glaucoma and myopia: a narrative review. Wmj 106 85 89, 95

5. LibbyRT

GouldDB

AndersonMG

JohnSW

2005 Complex genetics of glaucoma susceptibility. Annu Rev Genomics Hum Genet 6 15 44

6. BolandMV

QuigleyHA

2007 Risk factors and open-angle glaucoma: classification and application. J Glaucoma 16 406 418

7. MayP

WoldtE

MatzRL

BoucherP

2007 The LDL receptor-related protein (LRP) family: an old family of proteins with new physiological functions. Ann Med 39 219 228

8. FisherCE

HowieSE

2006 The role of megalin (LRP-2/Gp330) during development. Dev Biol 296 279 297

9. ChristensenEI

BirnH

2002 Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol 3 256 266

10. KantarciS

Al-GazaliL

HillRS

DonnaiD

BlackGC

2007 Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nat Genet 39 957 959

11. DonnaiD

BarrowM

1993 Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder? Am J Med Genet 47 679 682

12. PoberBR

LongoniM

NoonanKM

2009 A review of Donnai-Barrow and facio-oculo-acoustico-renal (DB/FOAR) syndrome: clinical features and differential diagnosis. Birth Defects Res A Clin Mol Teratol 85 76 81

13. XuL

WangY

WangS

WangY

JonasJB

2007 High myopia and glaucoma susceptibility the Beijing Eye Study. Ophthalmology 114 216 220

14. LinkBA

GrayMP

SmithRS

JohnSW

2004 Intraocular pressure in zebrafish: comparison of inbred strains and identification of a reduced melanin mutant with raised IOP. Invest Ophthalmol Vis Sci 45 4415 4422

15. GrayMP

SmithRS

SoulesKA

JohnSW

LinkB

2009 The aqueous humor outflow pathway of zebrafish. Invest Ophthalmol Vis Sci

16. SoulesKA

LinkBA

2005 Morphogenesis of the anterior segment in the zebrafish eye. BMC Dev Biol 5 12

17. RaymondPA

BarthelLK

BernardosRL

PerkowskiJJ

2006 Molecular characterization of retinal stem cells and their niches in adult zebrafish. BMC Dev Biol 6 36

18. JohnsPR

FernaldRD

1981 Genesis of rods in teleost fish retina. Nature 293 141 142

19. MorrisAC

ScholzTL

BrockerhoffSE

FadoolJM

2008 Genetic dissection reveals two separate pathways for rod and cone regeneration in the teleost retina. Dev Neurobiol 68 605 619

20. OttesonDC

D'CostaAR

HitchcockPF

2001 Putative stem cells and the lineage of rod photoreceptors in the mature retina of the goldfish. Dev Biol 232 62 76

21. GajeraCR

EmichH

LioubinskiO

ChristA

Beckervordersandforth-BonkR

2010 LRP2 in ependymal cells regulates BMP signaling in the adult neurogenic niche. J Cell Sci 123 1922 1930

22. BoscoA

InmanDM

SteeleMR

WuG

SotoI

2008 Reduced retina microglial activation and improved optic nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. Invest Ophthalmol Vis Sci 49 1437 1446

23. SchluesenerHJ

SeidK

MeyermannR

1999 Effects of autoantigen and dexamethasone treatment on expression of endothelial-monocyte activating polypeptide II and allograft-inflammatory factor-1 by activated macrophages and microglial cells in lesions of experimental autoimmune encephalomyelitis, neuritis and uveitis. Acta Neuropathol 97 119 126

24. IgnatiusMJ

Gebicke-HarterPJ

SkeneJH

SchillingJW

WeisgraberKH

1986 Expression of apolipoprotein E during nerve degeneration and regeneration. Proc Natl Acad Sci U S A 83 1125 1129

25. KuhrtH

HartigW

GrimmD

FaudeF

KasperM

1997 Changes in CD44 and ApoE immunoreactivities due to retinal pathology of man and rat. J Hirnforsch 38 223 229

26. PernetV

BourgeoisP

Di PoloA

2007 A role for polyamines in retinal ganglion cell excitotoxic death. J Neurochem 103 1481 1490

27. ZhangW

BabanB

RojasM

TofighS

VirmaniSK

2009 Arginase activity mediates retinal inflammation in endotoxin-induced uveitis. Am J Pathol 175 891 902

28. OsborneNN

BlockF

SontagKH

1991 Reduction of ocular blood flow results in glial fibrillary acidic protein (GFAP) expression in rat retinal Muller cells. Vis Neurosci 7 637 639

29. TaniharaH

HangaiM

SawaguchiS

AbeH

KageyamaM

1997 Up-regulation of glial fibrillary acidic protein in the retina of primate eyes with experimental glaucoma. Arch Ophthalmol 115 752 756

30. TakedaM

KatoH

TakamiyaA

YoshidaA

KiyamaH

2000 Injury-specific expression of activating transcription factor-3 in retinal ganglion cells and its colocalized expression with phosphorylated c-Jun. Invest Ophthalmol Vis Sci 41 2412 2421

31. VeldmanMB

BembenMA

ThompsonRC

GoldmanD

2007 Gene expression analysis of zebrafish retinal ganglion cells during optic nerve regeneration identifies KLF6a and KLF7a as important regulators of axon regeneration. Dev Biol 312 596 612

32. KuehnMH

KimCY

OstojicJ

BellinM

AlwardWL

2006 Retinal synthesis and deposition of complement components induced by ocular hypertension. Exp Eye Res 83 620 628

33. StasiK

NagelD

YangX

WangRF

RenL

2006 Complement component 1Q (C1Q) upregulation in retina of murine, primate, and human glaucomatous eyes. Invest Ophthalmol Vis Sci 47 1024 1029

34. StevensB

AllenNJ

VazquezLE

HowellGR

ChristophersonKS

2007 The classical complement cascade mediates CNS synapse elimination. Cell 131 1164 1178

35. HerdegenT

BastmeyerM

BahrM

StuermerC

BravoR

1993 Expression of JUN, KROX, and CREB transcription factors in goldfish and rat retinal ganglion cells following optic nerve lesion is related to axonal sprouting. J Neurobiol 24 528 543

36. KoistinahoJ

HokfeltT

1997 Altered gene expression in brain ischemia. Neuroreport 8: i- viii

37. BormannP

ZumstegVM

RothLW

ReinhardE

1998 Target contact regulates GAP-43 and alpha-tubulin mRNA levels in regenerating retinal ganglion cells. J Neurosci Res 52 405 419

38. DosterSK

LozanoAM

AguayoAJ

WillardMB

1991 Expression of the growth-associated protein GAP-43 in adult rat retinal ganglion cells following axon injury. Neuron 6 635 647

39. MooreDL

BlackmoreMG

HuY

KaestnerKH

BixbyJL

2009 KLF family members regulate intrinsic axon regeneration ability. Science 326 298 301

40. FischerD

PetkovaV

ThanosS

BenowitzLI

2004 Switching mature retinal ganglion cells to a robust growth state in vivo: gene expression and synergy with RhoA inactivation. J Neurosci 24 8726 8740

41. RollsA

CahalonL

BakalashS

AvidanH

LiderO

2006 A sulfated disaccharide derived from chondroitin sulfate proteoglycan protects against inflammation-associated neurodegeneration. Faseb J 20 547 549

42. DabinI

BarnstableCJ

1995 Rat retinal Muller cells express Thy-1 following neuronal cell death. Glia 14 23 32

43. SchlampCL

JohnsonEC

LiY

MorrisonJC

NickellsRW

2001 Changes in Thy1 gene expression associated with damaged retinal ganglion cells. Mol Vis 7 192 201

44. KokeJR

MosierAL

GarciaDM

2010 Intermediate filaments of zebrafish retinal and optic nerve astrocytes and Muller glia: differential distribution of cytokeratin and GFAP. BMC Res Notes 3 50

45. LevineRL

1989 Organization of astrocytes in the visual pathways of the goldfish: an immunohistochemical study. J Comp Neurol 285 231 245

46. LilloC

VelascoA

JimenoD

LaraJM

AijonJ

1998 Ultrastructural organization of the optic nerve of the tench (Cyprinidae, Teleostei). J Neurocytol 27 593 604

47. DownsJC

RobertsMD

BurgoyneCF

2008 Mechanical environment of the optic nerve head in glaucoma. Optom Vis Sci 85 425 435

48. EasterSSJr

RusoffAC

KishPE

1981 The growth and organization of the optic nerve and tract in juvenile and adult goldfish. J Neurosci 1 793 811

49. MaggsA

ScholesJ

1986 Glial domains and nerve fiber patterns in the fish retinotectal pathway. J Neurosci 6 424 438

50. SunD

Lye-BarthelM

MaslandRH

JakobsTC

2009 The morphology and spatial arrangement of astrocytes in the optic nerve head of the mouse. J Comp Neurol 516 1 19

51. HowellGR

LibbyRT

JakobsTC

SmithRS

PhalanFC

2007 Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol 179 1523 1537

52. NickellsRW

2007 From ocular hypertension to ganglion cell death: a theoretical sequence of events leading to glaucoma. Can J Ophthalmol 42 278 287

53. QuigleyHA

2005 Glaucoma: macrocosm to microcosm the Friedenwald lecture. Invest Ophthalmol Vis Sci 46 2662 2670

54. ColavincenzoJ

LevineRL

2000 Myelin debris clearance during Wallerian degeneration in the goldfish visual system. J Neurosci Res 59 47 62

55. UdvadiaAJ

2008 3.6 kb genomic sequence from Takifugu capable of promoting axon growth-associated gene expression in developing and regenerating zebrafish neurons. Gene Expr Patterns 8 382 388

56. BeckerCG

BeckerT

2007 Growth and pathfinding of regenerating axons in the optic projection of adult fish. J Neurosci Res 85 2793 2799

57. HysiPG

YoungTL

MackeyDA

AndrewT

Fernandez-MedardeA

2010 A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. Nat Genet 42 902 905

58. SoloukiAM

VerhoevenVJ

van DuijnCM

VerkerkAJ

IkramMK

2010 A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14. Nat Genet 42 897 901

59. ThorleifssonG

WaltersGB

HewittAW

MassonG

HelgasonA

2010 Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet 42 906 909

60. EasterSSJr

HitchcockPF

1986 The myopic eye of the Black Moor goldfish. Vision Res 26 1831 1833

61. RaymondPA

HitchcockPF

PalopoliMF

1988 Neuronal cell proliferation and ocular enlargement in Black Moor goldfish. J Comp Neurol 276 231 238

62. ThanosS

NaskarR

2004 Correlation between retinal ganglion cell death and chronically developing inherited glaucoma in a new rat mutant. Exp Eye Res 79 119 129

63. MiiA

NakajimaT

FujitaY

IinoY

KamimuraK

2007 Genetic association of low-density lipoprotein receptor-related protein 2 (LRP2) with plasma lipid levels. J Atheroscler Thromb 14 310 316

64. KamataniY

MatsudaK

OkadaY

KuboM

HosonoN

2010 Genome-wide association study of hematological and biochemical traits in a Japanese population. Nat Genet 42 210 215

65. PatelN

HejkalT

KatzA

MargalitE

2007 Ocular manifestations of Donnai-Barrow syndrome. J Child Neurol 22 462 464

66. RymerJ

WildsoetCF

2005 The role of the retinal pigment epithelium in eye growth regulation and myopia: a review. Vis Neurosci 22 251 261

67. AnzenbergerU

Bit-AvragimN

RohrS

RudolphF

DehmelB

2006 Elucidation of megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros. J Cell Sci 119 2127 2137

68. CarroE

SpuchC

TrejoJL

AntequeraD

Torres-AlemanI

2005 Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I. J Neurosci 25 10884 10893

69. ChristensenEI

WillnowTE

1999 Essential role of megalin in renal proximal tubule for vitamin homeostasis. J Am Soc Nephrol 10 2224 2236

70. HammadSM

RanganathanS

LoukinovaE

TwalWO

ArgravesWS

1997 Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein receptor-related protein-2/megalin. A mechanism to prevent pathological accumulation of amyloid beta-peptide. J Biol Chem 272 18644 18649

71. ZarbalisK

MaySR

ShenY

EkkerM

RubensteinJL

2004 A focused and efficient genetic screening strategy in the mouse: identification of mutations that disrupt cortical development. PLoS Biol 2 e219 doi:10.1371/journal.pbio.0020219

72. DirnaglU

SimonRP

HallenbeckJM

2003 Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 26 248 254

73. RothS

2004 Endogenous neuroprotection in the retina. Brain Res Bull 62 461 466

74. HitchcockPF

RaymondPA

2004 The teleost retina as a model for developmental and regeneration biology. Zebrafish 1 257 271

75. JohnSW

SmithRS

SavinovaOV

HawesNL

ChangB

1998 Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice. Invest Ophthalmol Vis Sci 39 951 962

76. AndersonMG

SmithRS

HawesNL

ZabaletaA

ChangB

2002 Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. Nat Genet 30 81 85

77. BuckinghamBP

InmanDM

LambertW

OglesbyE

CalkinsDJ

2008 Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma. J Neurosci 28 2735 2744

78. SotoI

OglesbyE

BuckinghamBP

SonJL

RobersonED

2008 Retinal ganglion cells downregulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model. J Neurosci 28 548 561

79. MurrayM

1982 A quantitative study of regenerative sprouting by optic axons in goldfish. J Comp Neurol 209 352 362

80. ZhouLX

WangZR

2002 [Changes in number and distribution of retinal ganglion cells after optic nerve crush in zebrafish]. Shi Yan Sheng Wu Xue Bao 35 159 162

81. BerkelaarM

ClarkeDB

WangYC

BrayGM

AguayoAJ

1994 Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats. J Neurosci 14 4368 4374

82. QuigleyHA