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Lens-Specific Transcription Factors and Their Roles in Diagnosis and Treatment of Human Congenital Cataract

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Lens Epithelium and Posterior Capsular Opacification

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Abstract

Specific DNA-binding transcription factors (TFs) are critical components of gene regulatory networks (GRNs) that govern lens growth and differentiation. Lens placode formation is controlled by Pax6, Six3, and Sox2. Lens vesicle formation and its separation from the surface ectoderm are regulated by AP-2α, Foxe3, and retinoic acid/retinoid-activated nuclear receptors. The lens precursor cells exit cell cycle via a coordinated action of Gata3, Pitx3, and Prox1. Lens fiber cell differentiation is controlled by ATF4/CREB2, c-Maf, Gata3, Hsf4, Pax6, Pitx3, Prox1, and Sox1. Lens morphogenesis requires intricate temporal and spatial control of gene expression that is executed through multiple links between TFs and extracellular signaling, including BMP, FGF, Notch, and Wnt pathways. Disrupted function of lens-preferred TFs results in multiple lens developmental abnormalities that range from the lack of lens formation, lost of primordial lens (aphakia), incomplete separation of the lens vesicle from the surface ectoderm (corneal-lenticular stalk), disrupted lens fiber cell differentiation, and retention of subcellular organelles including the nuclei. These developmental abnormalities are not compatible with lens transparency and result in congenital cataracts. These cataracts affect 1:2,500 individuals and are difficult to manage due to the age of the child and eye growth considerations, possible associated microcornea or microphthalmia, and risks of glaucoma and amblyopia. For example, up to ~40 % of children with bilateral cataracts develop glaucoma following surgery, particularly when cataracts are removed early in life. This review describes normal and abnormal lens formation through the perspective of TFs preferentially expressed in the lens, their contributions to the human pediatric cataracts, and current strategies in human genetic and clinical studies to identify novel cataract-associated genes to better understand molecular basis of these defects and its treatments.

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References

  1. Bassnett S, Shi Y, Vrensen GF (2011) Biological glass: structural determinants of eye lens transparency. Philos Trans R Soc Lond B Biol Sci 366:1250–1264

    PubMed Central  PubMed  Google Scholar 

  2. Bassnett S (2009) On the mechanism of organelle degradation in the vertebrate lens. Exp Eye Res 88:133–139

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Shiels A, Hejtmancik JF (2013) Genetics of human cataract. Clin Genet 84:120–127

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Francis PJ, Berry V, Moore AT, Bhattacharya S (1999) Lens biology: development and human cataractogenesis. Trends Genet 15:191–196

    CAS  PubMed  Google Scholar 

  5. Foster A, Gilbert C, Rahi J (1997) Epidemiology of cataract in childhood: a global perspective. J Cataract Refract Surg 23(Suppl 1):601–604

    PubMed  Google Scholar 

  6. Abrahamsson M, Magnusson G, Sjostrom A, Popovic Z, Sjostrand J (1999) The occurrence of congenital cataract in western Sweden. Acta Ophthalmol Scand 77:578–580

    CAS  PubMed  Google Scholar 

  7. Wirth MG, Russell-Eggitt IM, Craig JE, Elder JE, Mackey DA (2002) Aetiology of congenital and paediatric cataract in an Australian population. Br J Ophthalmol 86:782–786

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Grainger RM (1992) Embryonic lens induction: shedding light on vertebrate tissue determination. Trends Genet 8:349–355

    CAS  PubMed  Google Scholar 

  9. Cvekl A, Piatigorsky J (1996) Lens development and crystallin gene expression: many roles for Pax-6. Bioessays 18:621–630

    CAS  PubMed  Google Scholar 

  10. Ashery-Padan R, Gruss P (2001) Pax6 lights-up the way for eye development. Curr Opin Cell Biol 13:706–714

    CAS  PubMed  Google Scholar 

  11. Lovicu FJ, McAvoy JW (2005) Growth factor regulation of lens development. Dev Biol 280:1–14

    CAS  PubMed  Google Scholar 

  12. Donner AL, Lachke SA, Maas RL (2006) Lens induction in vertebrates: variations on a conserved theme of signaling events. Semin Cell Dev Biol 17:676–685

    CAS  PubMed  Google Scholar 

  13. Griep AE (2006) Cell cycle regulation in the developing lens. Semin Cell Dev Biol 17:686–697

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Medina-Martinez O, Jamrich M (2007) Foxe view of lens development and disease. Development 134:1455–1463

    CAS  PubMed  Google Scholar 

  15. Cvekl A, Duncan MK (2007) Genetic and epigenetic mechanisms of gene regulation during lens development. Prog Retin Eye Res 26:555–597

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Cvekl A, Mitton KP (2010) Epigenetic regulatory mechanisms in vertebrate eye development and disease. Heredity (Edinb) 105:135–151

    CAS  Google Scholar 

  17. Smith AN, Radice G, Lang RA (2010) Which FGF ligands are involved in lens induction? Dev Biol 337:195–198

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Shaham O, Menuchin Y, Farhy C, Ashery-Padan R (2012) Pax6: a multi-level regulator of ocular development. Prog Retin Eye Res 31:351–376

    CAS  PubMed  Google Scholar 

  19. Liu W, Lagutin OV, Mende M, Streit A, Oliver G (2006) Six3 activation of Pax6 expression is essential for mammalian lens induction and specification. EMBO J 25:5383–5395

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Yamada R, Mizutani-Koseki Y, Hasegawa T, Osumi N, Koseki H et al (2003) Cell-autonomous involvement of Mab21l1 is essential for lens placode development. Development 130:1759–1770

    CAS  PubMed  Google Scholar 

  21. Wurm A, Sock E, Fuchshofer R, Wegner M, Tamm ER (2008) Anterior segment dysgenesis in the eyes of mice deficient for the high-mobility-group transcription factor Sox11. Exp Eye Res 86:895–907

    CAS  PubMed  Google Scholar 

  22. Saravanamuthu SS, Le TT, Gao CY, Cojocaru RI, Pandiyan P et al (2012) Conditional ablation of the Notch2 receptor in the ocular lens. Dev Biol 362:219–229

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Rowan S, Conley KW, Le TT, Donner AL, Maas RL et al (2008) Notch signaling regulates growth and differentiation in the mammalian lens. Dev Biol 321:111–122

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Kuszak JR, Zoltoski RK, Tiedemann CE (2004) Development of lens sutures. Int J Dev Biol 48:889–902

    PubMed  Google Scholar 

  25. Xie Q, Cvekl A (2011) The orchestration of mammalian tissue morphogenesis through a series of coherent feed-forward loops. J Biol Chem 286:43259–43271

    CAS  PubMed Central  PubMed  Google Scholar 

  26. He S, Pirity MK, Wang WL, Wolf L, Chauhan BK et al (2010) Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation. Epigenetics Chromatin 3:21

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Nishimoto S, Kawane K, Watanabe-Fukunaga R, Fukuyama H, Ohsawa Y et al (2003) Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens. Nature 424:1071–1074

    CAS  PubMed  Google Scholar 

  28. Wang WL, Li Q, Xu J, Cvekl A (2010) Lens fiber cell differentiation and denucleation are disrupted through expression of the N-terminal nuclear receptor box of NCOA6 and result in p53-dependent and p53-independent apoptosis. Mol Biol Cell 21:2453–2468

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Tanaka T, Tsujimura T, Takeda K, Sugihara A, Maekawa A et al (1998) Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres. Genes Cells 3:801–810

    CAS  PubMed  Google Scholar 

  30. Churchill A, Graw J (2011) Clinical and experimental advances in congenital and paediatric cataracts. Philos Trans R Soc Lond B Biol Sci 366:1234–1249

    PubMed Central  PubMed  Google Scholar 

  31. Graw J (2009) Mouse models of cataract. J Genet 88:469–486

    CAS  PubMed  Google Scholar 

  32. Graw J (2009) Genetics of crystallins: cataract and beyond. Exp Eye Res 88:173–189

    CAS  PubMed  Google Scholar 

  33. Reddy MA, Francis PJ, Berry V, Bhattacharya SS, Moore AT (2004) Molecular genetic basis of inherited cataract and associated phenotypes. Surv Ophthalmol 49:300–315

    PubMed  Google Scholar 

  34. Azuma N, Hirakiyama A, Inoue T, Asaka A, Yamada M (2000) Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies. Hum Mol Genet 9:363–366

    CAS  PubMed  Google Scholar 

  35. Semina EV, Brownell I, Mintz-Hittner HA, Murray JC, Jamrich M (2001) Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum Mol Genet 10:231–236

    CAS  PubMed  Google Scholar 

  36. Bu L, Jin Y, Shi Y, Chu R, Ban A et al (2002) Mutant DNA-binding domain of HSF4 is associated with autosomal dominant lamellar and Marner cataract. Nat Genet 31:276–278

    CAS  PubMed  Google Scholar 

  37. Jamieson RV, Perveen R, Kerr B, Carette M, Yardley J et al (2002) Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma. Hum Mol Genet 11:33–42

    CAS  PubMed  Google Scholar 

  38. Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA et al (2005) Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet 76:1008–1022

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Glaser T, Jepeal L, Edwards JG, Young SR, Favor J et al (1994) PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet 7:463–471

    CAS  PubMed  Google Scholar 

  40. Semina EV, Ferrell RE, Mintz-Hittner HA, Bitoun P, Alward WL et al (1998) A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD. Nat Genet 19:167–170

    CAS  PubMed  Google Scholar 

  41. Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker HJ et al (2008) TFAP2A mutations result in branchio-oculo-facial syndrome. Am J Hum Genet 82:1171–1177

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Pineda-Alvarez DE, Solomon BD, Roessler E, Balog JZ, Hadley DW et al (2011) A broad range of ophthalmologic anomalies is part of the holoprosencephaly spectrum. Am J Med Genet A 155A:2713–2720

    PubMed  Google Scholar 

  43. Ragge NK, Lorenz B, Schneider A, Bushby K, de Sanctis L et al (2005) SOX2 anophthalmia syndrome. Am J Med Genet A 135:1–7, discussion 8

    PubMed  Google Scholar 

  44. Slavotinek AM (2011) Eye development genes and known syndromes. Mol Genet Metab 104:448–456

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Hever AM, Williamson KA, van Heyningen V (2006) Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2. Clin Genet 69:459–470

    CAS  PubMed  Google Scholar 

  46. Epstein J, Cai J, Glaser T, Jepeal L, Maas R (1994) Identification of a Pax paired domain recognition sequence and evidence for DNA-dependent conformational changes. J Biol Chem 269:8355–8361

    CAS  PubMed  Google Scholar 

  47. Epstein JA, Glaser T, Cai J, Jepeal L, Walton DS et al (1994) Two independent and interactive DNA-binding subdomains of the Pax6 paired domain are regulated by alternative splicing. Genes Dev 8:2022–2034

    CAS  PubMed  Google Scholar 

  48. Hogan BL, Horsburgh G, Cohen J, Hetherington CM, Fisher G et al (1986) Small eyes (Sey): a homozygous lethal mutation on chromosome 2 which affects the differentiation of both lens and nasal placodes in the mouse. J Embryol Exp Morphol 97:95–110

    CAS  PubMed  Google Scholar 

  49. van Heyningen V, Williamson KA (2002) PAX6 in sensory development. Hum Mol Genet 11:1161–1167

    PubMed  Google Scholar 

  50. Hanson I, Van Heyningen V (1995) Pax6: more than meets the eye. Trends Genet 11:268–272

    CAS  PubMed  Google Scholar 

  51. Gregory-Evans CY, Wang X, Wasan K, Zhao J, Metcalfe AL, Gregory-Evans K (2014) Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects. J Clin Invest 124:111–116

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Chauhan BK, Yang Y, Cveklova K, Cvekl A (2004) Functional interactions between alternatively spliced forms of Pax6 in crystallin gene regulation and in haploinsufficiency. Nucleic Acids Res 32:1696–1709

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Chauhan BK, Yang Y, Cveklova K, Cvekl A (2004) Functional properties of natural human PAX6 and PAX6(5a) mutants. Invest Ophthalmol Vis Sci 45:385–392

    PubMed Central  PubMed  Google Scholar 

  54. Hingorani M, Hanson I, van Heyningen V (2012) Aniridia. Eur J Hum Genet 20:1011–1017

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Kleinjan DA, Seawright A, Schedl A, Quinlan RA, Danes S et al (2001) Aniridia-associated translocations, DNase hypersensitivity, sequence comparison and transgenic analysis redefine the functional domain of PAX6. Hum Mol Genet 10:2049–2059

    CAS  PubMed  Google Scholar 

  56. Lauderdale JD, Wilensky JS, Oliver ER, Walton DS, Glaser T (2000) 3′ deletions cause aniridia by preventing PAX6 gene expression. Proc Natl Acad Sci U S A 97:13755–13759

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Schilter K, Reis L, Schneider A, Bardakjian T, Abdul-Rahman O et al (2013) Whole-genome copy number variation analysis in anophthalmia and microphthalmia. Clin Genet 84:473–481

    CAS  PubMed  Google Scholar 

  58. Shaham O, Smith AN, Robinson ML, Taketo MM, Lang RA et al (2009) Pax6 is essential for lens fiber cell differentiation. Development 136:2567–2578

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Huang J, Rajagopal R, Liu Y, Dattilo LK, Shaham O et al (2011) The mechanism of lens placode formation: a case of matrix-mediated morphogenesis. Dev Biol 355:32–42

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Xie Q, Yang Y, Huang J, Ninkovic J, Walcher T et al (2013) Pax6 interactions with chromatin and identification of its novel direct target genes in lens and forebrain. PLoS One 8:e54507

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Wolf L, Harrison W, Huang J, Xie Q, Xiao N et al (2013) Histone posttranslational modifications and cell fate determination: lens induction requires the lysine acetyltransferases CBP and p300. Nucleic Acids Res 41:10199–10214

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Shaham O, Gueta K, Mor E, Oren-Giladi P, Grinberg D et al (2013) Pax6 regulates gene expression in the vertebrate lens through miR-204. PLoS Genet 9:e1003357

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Wolf LV, Yang Y, Wang J, Xie Q, Braunger B et al (2009) Identification of pax6-dependent gene regulatory networks in the mouse lens. PLoS One 4:e4159

    PubMed Central  PubMed  Google Scholar 

  64. Simeone A, Acampora D, Mallamaci A, Stornaiuolo A, D’Apice MR et al (1993) A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo. EMBO J 12:2735–2747

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Matsuo I, Kuratani S, Kimura C, Takeda N, Aizawa S (1995) Mouse Otx2 functions in the formation and patterning of rostral head. Genes Dev 9:2646–2658

    CAS  PubMed  Google Scholar 

  66. Montalta-He H, Leemans R, Loop T, Strahm M, Certa U et al (2002) Evolutionary conservation of otd/Otx2 transcription factor action: a genome-wide microarray analysis in Drosophila. Genome Biol 3:RESEARCH0015

    PubMed Central  PubMed  Google Scholar 

  67. Beby F, Lamonerie T (2013) The homeobox gene Otx2 in development and disease. Exp Eye Res 111:9–16

    CAS  PubMed  Google Scholar 

  68. Schilter KF, Schneider A, Bardakjian T, Soucy JF, Tyler RC et al (2011) OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype. Clin Genet 79:158–168

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Scaffidi P, Bianchi ME (2001) Spatially precise DNA bending is an essential activity of the sox2 transcription factor. J Biol Chem 276:47296–47302

    CAS  PubMed  Google Scholar 

  70. Kelberman D, Rizzoti K, Avilion A, Bitner-Glindzicz M, Cianfarani S et al (2006) Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest 116:2442–2455

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Kiernan AE, Pelling AL, Leung KK, Tang AS, Bell DM et al (2005) Sox2 is required for sensory organ development in the mammalian inner ear. Nature 434:1031–1035

    CAS  PubMed  Google Scholar 

  72. Taranova OV, Magness ST, Fagan BM, Wu Y, Surzenko N et al (2006) SOX2 is a dose-dependent regulator of retinal neural progenitor competence. Genes Dev 20:1187–1202

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Schneider A, Bardakjian T, Reis LM, Tyler RC, Semina EV (2009) Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia. Am J Med Genet A 149A:2706–2715

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Wang P, Liang X, Yi J, Zhang Q (2008) Novel SOX2 mutation associated with ocular coloboma in a Chinese family. Arch Ophthalmol 126:709–713

    CAS  PubMed  Google Scholar 

  75. Danno H, Michiue T, Hitachi K, Yukita A, Ishiura S et al (2008) Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression. Proc Natl Acad Sci U S A 105:5408–5413

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Kamachi Y, Uchikawa M, Tanouchi A, Sekido R, Kondoh H (2001) Pax6 and SOX2 form a co-DNA-binding partner complex that regulates initiation of lens development. Genes Dev 15:1272–1286

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Loosli F, Winkler S, Wittbrodt J (1999) Six3 overexpression initiates the formation of ectopic retina. Genes Dev 13:649–654

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Oliver G, Loosli F, Koster R, Wittbrodt J, Gruss P (1996) Ectopic lens induction in fish in response to the murine homeobox gene Six3. Mech Dev 60:233–239

    CAS  PubMed  Google Scholar 

  79. Lagutin O, Zhu CC, Furuta Y, Rowitch DH, McMahon AP et al (2001) Six3 promotes the formation of ectopic optic vesicle-like structures in mouse embryos. Dev Dyn 221:342–349

    CAS  PubMed  Google Scholar 

  80. Lagutin OV, Zhu CC, Kobayashi D, Topczewski J, Shimamura K et al (2003) Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development. Genes Dev 17:368–379

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T et al (1999) Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet 22:196–198

    CAS  PubMed  Google Scholar 

  82. Li X, Oghi KA, Zhang J, Krones A, Bush KT et al (2003) Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 426:247–254

    CAS  PubMed  Google Scholar 

  83. Rayapureddi JP, Kattamuri C, Steinmetz BD, Frankfort BJ, Ostrin EJ et al (2003) Eyes absent represents a class of protein tyrosine phosphatases. Nature 426:295–298

    CAS  PubMed  Google Scholar 

  84. Xu PX, Adams J, Peters H, Brown MC, Heaney S et al (1999) Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nat Genet 23:113–117

    CAS  PubMed  Google Scholar 

  85. Orten DJ, Fischer SM, Sorensen JL, Radhakrishna U, Cremers CW et al (2008) Branchio-oto-renal syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR. Hum Mutat 29:537–544

    CAS  PubMed  Google Scholar 

  86. Vincent C, Kalatzis V, Abdelhak S, Chaib H, Compain S et al (1997) BOR and BO syndromes are allelic defects of EYA1. Eur J Hum Genet 5:242–246

    CAS  PubMed  Google Scholar 

  87. Reis LM, Tyler RC, Muheisen S, Raggio V, Salviati L et al (2013) Whole exome sequencing in dominant cataract identifies a new causative factor, CRYBA2, and a variety of novel alleles in known genes. Hum Genet 132:761–770

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Rayapureddi JP, Hegde RS (2006) Branchio-oto-renal syndrome associated mutations in eyes absent 1 result in loss of phosphatase activity. FEBS Lett 580:3853–3859

    CAS  PubMed  Google Scholar 

  89. Zhang J, Hagopian-Donaldson S, Serbedzija G, Elsemore J, Plehn-Dujowich D et al (1996) Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2. Nature 381:238–241

    CAS  PubMed  Google Scholar 

  90. Bassett EA, Williams T, Zacharias AL, Gage PJ, Fuhrmann S et al (2010) AP-2alpha knockout mice exhibit optic cup patterning defects and failure of optic stalk morphogenesis. Hum Mol Genet 19:1791–1804

    CAS  PubMed Central  PubMed  Google Scholar 

  91. West-Mays JA, Zhang J, Nottoli T, Hagopian-Donaldson S, Libby D et al (1999) AP-2alpha transcription factor is required for early morphogenesis of the lens vesicle. Dev Biol 206:46–62

    CAS  PubMed  Google Scholar 

  92. Gestri G, Osborne RJ, Wyatt AW, Gerrelli D, Gribble S et al (2009) Reduced TFAP2A function causes variable optic fissure closure and retinal defects and sensitizes eye development to mutations in other morphogenetic regulators. Hum Genet 126:791–803

    PubMed Central  PubMed  Google Scholar 

  93. Al-Dosari MS, Almazyad M, Al-Ebdi L, Mohamed JY, Al-Dahmash S et al (2010) Ocular manifestations of branchio-oculo-facial syndrome: report of a novel mutation and review of the literature. Mol Vis 16:813–818

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Dumitrescu AV, Milunsky JM, Longmuir SQ, Drack AV (2012) A family with branchio-oculo-facial syndrome with primarily ocular involvement associated with mutation of the TFAP2A gene. Ophthalmic Genet 33:100–106

    CAS  PubMed  Google Scholar 

  95. Blixt A, Mahlapuu M, Aitola M, Pelto-Huikko M, Enerback S et al (2000) A forkhead gene, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle. Genes Dev 14:245–254

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Brownell I, Dirksen M, Jamrich M (2000) Forkhead Foxe3 maps to the dysgenetic lens locus and is critical in lens development and differentiation. Genesis 27:81–93

    CAS  PubMed  Google Scholar 

  97. Ormestad M, Blixt A, Churchill A, Martinsson T, Enerback S et al (2002) Foxe3 haploinsufficiency in mice: a model for Peters’ anomaly. Invest Ophthalmol Vis Sci 43:1350–1357

    PubMed  Google Scholar 

  98. Wada K, Maeda YY, Watanabe K, Oshio T, Ueda T et al (2011) A deletion in a cis element of Foxe3 causes cataracts and microphthalmia in rct mice. Mamm Genome 22:693–702

    CAS  PubMed  Google Scholar 

  99. Vihtelic TS (2008) Teleost lens development and degeneration. Int Rev Cell Mol Biol 269:341–373

    CAS  PubMed  Google Scholar 

  100. Iseri SU, Osborne RJ, Farrall M, Wyatt AW, Mirza G et al (2009) Seeing clearly: the dominant and recessive nature of FOXE3 in eye developmental anomalies. Hum Mutat 30:1378–1386

    CAS  PubMed  Google Scholar 

  101. Reis LM, Tyler RC, Schneider A, Bardakjian T, Stoler JM et al (2010) FOXE3 plays a significant role in autosomal recessive microphthalmia. Am J Med Genet A 152A:582–590

    PubMed Central  PubMed  Google Scholar 

  102. Valleix S, Niel F, Nedelec B, Algros MP, Schwartz C et al (2006) Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans. Am J Hum Genet 79:358–364

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Ali M, Buentello-Volante B, McKibbin M, Rocha-Medina JA, Fernandez-Fuentes N et al (2010) Homozygous FOXE3 mutations cause non-syndromic, bilateral, total sclerocornea, aphakia, microphthalmia and optic disc coloboma. Mol Vis 16:1162–1168

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Pontoriero GF, Deschamps P, Ashery-Padan R, Wong R, Yang Y et al (2008) Cell autonomous roles for AP-2alpha in lens vesicle separation and maintenance of the lens epithelial cell phenotype. Dev Dyn 237:602–617

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Mathers PH, Grinberg A, Mahon KA, Jamrich M (1997) The Rx homeobox gene is essential for vertebrate eye development. Nature 387:603–607

    CAS  PubMed  Google Scholar 

  106. Amendt BA, Sutherland LB, Semina EV, Russo AF (1998) The molecular basis of Rieger syndrome. Analysis of Pitx2 homeodomain protein activities. J Biol Chem 273:20066–20072

    CAS  PubMed  Google Scholar 

  107. Semina EV, Reiter R, Leysens NJ, Alward WL, Small KW et al (1996) Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392–399

    CAS  PubMed  Google Scholar 

  108. Sakazume S, Sorokina E, Iwamoto Y, Semina EV (2007) Functional analysis of human mutations in homeodomain transcription factor PITX3. BMC Mol Biol 8:84

    PubMed Central  PubMed  Google Scholar 

  109. Semina EV, Reiter RS, Murray JC (1997) Isolation of a new homeobox gene belonging to the Pitx/Rieg family: expression during lens development and mapping to the aphakia region on mouse chromosome 19. Hum Mol Genet 6:2109–2116

    CAS  PubMed  Google Scholar 

  110. Rieger DK, Reichenberger E, McLean W, Sidow A, Olsen BR (2001) A double-deletion mutation in the Pitx3 gene causes arrested lens development in aphakia mice. Genomics 72:61–72

    CAS  PubMed  Google Scholar 

  111. Semina EV, Murray JC, Reiter R, Hrstka RF, Graw J (2000) Deletion in the promoter region and altered expression of Pitx3 homeobox gene in aphakia mice. Hum Mol Genet 9:1575–1585

    CAS  PubMed  Google Scholar 

  112. Varnum DS, Stevens LC (1968) Aphakia, a new mutation in the mouse. J Hered 59:147–150

    CAS  PubMed  Google Scholar 

  113. Zhao S, Maxwell S, Jimenez-Beristain A, Vives J, Kuehner E et al (2004) Generation of embryonic stem cells and transgenic mice expressing green fluorescence protein in midbrain dopaminergic neurons. Eur J Neurosci 19:1133–1140

    PubMed  Google Scholar 

  114. Berry V, Yang Z, Addison PK, Francis PJ, Ionides A et al (2004) Recurrent 17 bp duplication in PITX3 is primarily associated with posterior polar cataract (CPP4). J Med Genet 41:e109

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Addison PK, Berry V, Ionides AC, Francis PJ, Bhattacharya SS et al (2005) Posterior polar cataract is the predominant consequence of a recurrent mutation in the PITX3 gene. Br J Ophthalmol 89:138–141

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Finzi S, Li Y, Mitchell TN, Farr A, Maumenee IH et al (2005) Posterior polar cataract: genetic analysis of a large family. Ophthalmic Genet 26:125–130

    PubMed  Google Scholar 

  117. Burdon KP, McKay JD, Wirth MG, Russell-Eggit IM, Bhatti S et al (2006) The PITX3 gene in posterior polar congenital cataract in Australia. Mol Vis 12:367–371

    CAS  PubMed  Google Scholar 

  118. Summers KM, Withers SJ, Gole GA, Piras S, Taylor PJ (2008) Anterior segment mesenchymal dysgenesis in a large Australian family is associated with the recurrent 17 bp duplication in PITX3. Mol Vis 14:2010–2015

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Bidinost C, Matsumoto M, Chung D, Salem N, Zhang K et al (2006) Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities. Invest Ophthalmol Vis Sci 47:1274–1280

    PubMed  Google Scholar 

  120. Aldahmesh MA, Khan AO, Mohamed J, Alkuraya FS (2011) Novel recessive BFSP2 and PITX3 mutations: insights into mutational mechanisms from consanguineous populations. Genet Med 13:978–981

    CAS  PubMed  Google Scholar 

  121. Chauhan BK, Reed NA, Zhang W, Duncan MK, Kilimann MW et al (2002) Identification of genes downstream of Pax6 in the mouse lens using cDNA microarrays. J Biol Chem 277:11539–11548

    CAS  PubMed  Google Scholar 

  122. Wolf L, Harrison W, Huang J, Xie Q, Xiao N, Sun J, Kong L, Lachke SA, Kuracha MR, Govindarajan V, Brindle PK, Ashery-Padan R, Beebe DC, Overbeek PA, Cvekl A (2013) HIstone posttranslational modifications and cell fate determination: lens induction requires the lysine acetyltransferases CBP and p300. Nucleic Acids Res 41

    Google Scholar 

  123. Hooker L, Smoczer C, KhosrowShahian F, Wolanski M, Crawford MJ (2012) Microarray-based identification of Pitx3 targets during Xenopus embryogenesis. Dev Dyn 241:1487–1505

    CAS  PubMed  Google Scholar 

  124. Shi X, Luo Y, Howley S, Dzialo A, Foley S et al (2006) Zebrafish foxe3: roles in ocular lens morphogenesis through interaction with pitx3. Mech Dev 123:761–782

    CAS  PubMed  Google Scholar 

  125. Medina-Martinez O, Shah R, Jamrich M (2009) Pitx3 controls multiple aspects of lens development. Dev Dyn 238:2193–2201

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Ho HY, Chang KH, Nichols J, Li M (2009) Homeodomain protein Pitx3 maintains the mitotic activity of lens epithelial cells. Mech Dev 126:18–29

    CAS  PubMed  Google Scholar 

  127. Ahmad N, Aslam M, Muenster D, Horsch M, Khan MA, Carlsson P, BeckersJ GJ (2013) Pitx3 directly regulates Foxe3 during early lens development. Int J Dev Biol 57:741–751

    CAS  PubMed  Google Scholar 

  128. Sorokina EA, Muheisen S, Mlodik N, Semina EV (2011) MIP/Aquaporin 0 represents a direct transcriptional target of PITX3 in the developing lens. PLoS One 6:e21122

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Ring BZ, Cordes SP, Overbeek PA, Barsh GS (2000) Regulation of mouse lens fiber cell development and differentiation by the Maf gene. Development 127:307–317

    CAS  PubMed  Google Scholar 

  130. Fujimoto M, Izu H, Seki K, Fukuda K, Nishida T et al (2004) HSF4 is required for normal cell growth and differentiation during mouse lens development. EMBO J 23:4297–4306

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Fujimoto M, Oshima K, Shinkawa T, Wang BB, Inouye S et al (2008) Analysis of HSF4 binding regions reveals its necessity for gene regulation during development and heat shock response in mouse lenses. J Biol Chem 283:29961–29970

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Cui X, Wang L, Zhang J, Du R, Liao S et al (2013) HSF4 regulates DLAD expression and promotes lens de-nucleation. Biochim Biophys Acta 1832:1167–1172

    CAS  PubMed  Google Scholar 

  133. Smaoui N, Beltaief O, BenHamed S, M’Rad R, Maazoul F et al (2004) A homozygous splice mutation in the HSF4 gene is associated with an autosomal recessive congenital cataract. Invest Ophthalmol Vis Sci 45:2716–2721

    PubMed  Google Scholar 

  134. Yang Y, Cvekl A (2007) Large Maf transcription factors: cousins of AP-1 proteins and important regulators of cellular differentiation. Einstein J Biol Med 23:2–11

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Takeuchi T, Kudo T, Ogata K, Hamada M, Nakamura M et al (2009) Neither MafA/L-Maf nor MafB is essential for lens development in mice. Genes Cells 14:941–947

    CAS  PubMed  Google Scholar 

  136. Vinson C, Myakishev M, Acharya A, Mir AA, Moll JR et al (2002) Classification of human B-ZIP proteins based on dimerization properties. Mol Cell Biol 22:6321–6335

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Jamieson RV, Munier F, Balmer A, Farrar N, Perveen R et al (2003) Pulverulent cataract with variably associated microcornea and iris coloboma in a MAF mutation family. Br J Ophthalmol 87:411–412

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Lyon MF, Jamieson RV, Perveen R, Glenister PH, Griffiths R et al (2003) A dominant mutation within the DNA-binding domain of the bZIP transcription factor Maf causes murine cataract and results in selective alteration in DNA binding. Hum Mol Genet 12:585–594

    CAS  PubMed  Google Scholar 

  139. Perveen R, Favor J, Jamieson RV, Ray DW, Black GC (2007) A heterozygous c-Maf transactivation domain mutation causes congenital cataract and enhances target gene activation. Hum Mol Genet 16:1030–1038

    CAS  PubMed  Google Scholar 

  140. Hansen L, Eiberg H, Rosenberg T (2007) Novel MAF mutation in a family with congenital cataract-microcornea syndrome. Mol Vis 13:2019–2022

    CAS  PubMed  Google Scholar 

  141. Vanita V, Singh D, Robinson PN, Sperling K, Singh JR (2006) A novel mutation in the DNA-binding domain of MAF at 16q23.1 associated with autosomal dominant “cerulean cataract” in an Indian family. Am J Med Genet A 140:558–566

    PubMed  Google Scholar 

  142. Yang Y, Wolf LV, Cvekl A (2007) Distinct embryonic expression and localization of CBP and p300 histone acetyltransferases at the mouse alphaA-crystallin locus in lens. J Mol Biol 369:917–926

    CAS  PubMed Central  PubMed  Google Scholar 

  143. van Genderen MM, Kinds GF, Riemslag FC, Hennekam RC (2000) Ocular features in Rubinstein-Taybi syndrome: investigation of 24 patients and review of the literature. Br J Ophthalmol 84:1177–1184

    PubMed Central  PubMed  Google Scholar 

  144. Lachke SA, Ho JW, Kryukov GV, O’Connell DJ, Aboukhalil A et al (2012) iSyTE: integrated systems tool for eye gene discovery. Invest Ophthalmol Vis Sci 53:1617–1627

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Barolo S, Posakony JW (2002) Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling. Genes Dev 16:1167–1181

    CAS  PubMed  Google Scholar 

  146. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS et al (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS et al (2006) Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125:301–313

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Yun S, Saijoh Y, Hirokawa KE, Kopinke D, Murtaugh LC et al (2009) Lhx2 links the intrinsic and extrinsic factors that control optic cup formation. Development 136:3895–3906

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Lleras-Forero L, Tambalo M, Christophorou N, Chambers D, Houart C et al (2013) Neuropeptides: developmental signals in placode progenitor formation. Dev Cell 26:195–203

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Chen Q, Dowhan DH, Liang D, Moore DD, Overbeek PA (2002) CREB-binding protein/p300 co-activation of crystallin gene expression. J Biol Chem 277:24081–24089

    CAS  PubMed  Google Scholar 

  151. Parks MM, Johnson DA, Reed GW (1993) Long-term visual results and complications in children with aphakia. A function of cataract type. Ophthalmology 100:826–840, discussion 840-821

    CAS  PubMed  Google Scholar 

  152. Hosal BM, Biglan AW (2002) Risk factors for secondary membrane formation after removal of pediatric cataract. J Cataract Refract Surg 28:302–309

    PubMed  Google Scholar 

  153. Zetterstrom C, Lundvall A, Kugelberg M (2005) Cataracts in children. J Cataract Refract Surg 31:824–840

    PubMed  Google Scholar 

  154. Lambert SR, Buckley EG, Drews-Botsch C, DuBois L, Hartmann E et al (2010) The infant aphakia treatment study: design and clinical measures at enrollment. Arch Ophthalmol 128:21–27

    PubMed  Google Scholar 

  155. Lambert SR, Buckley EG, Drews-Botsch C, DuBois L, Hartmann EE et al (2010) A randomized clinical trial comparing contact lens with intraocular lens correction of monocular aphakia during infancy: grating acuity and adverse events at age 1 year. Arch Ophthalmol 128:810–818

    PubMed  Google Scholar 

  156. Ruddle JB, Staffieri SE, Crowston JG, Sherwin JC, Mackey DA (2013) Incidence and predictors of glaucoma following surgery for congenital cataract in the first year of life in Victoria, Australia. Clin Experiment Ophthalmol 41:653–661

    PubMed  Google Scholar 

  157. Beck AD, Freedman SF, Lynn MJ, Bothun E, Neely DE et al (2012) Glaucoma-related adverse events in the infant aphakia treatment study: 1-year results. Arch Ophthalmol 130:300–305

    PubMed Central  PubMed  Google Scholar 

  158. Sharma N, Pushker N, Dada T, Vajpayee RB, Dada VK (1999) Complications of pediatric cataract surgery and intraocular lens implantation. J Cataract Refract Surg 25:1585–1588

    CAS  PubMed  Google Scholar 

  159. Birch EE, Cheng C, Stager DR Jr, Felius J (2005) Visual acuity development after the implantation of unilateral intraocular lenses in infants and young children. J AAPOS 9:527–532

    PubMed  Google Scholar 

  160. Peltz SW, Morsy M, Welch EM, Jacobson A (2013) Ataluren as an agent for therapeutic nonsense suppression. Annu Rev Med 64:407–425

    CAS  PubMed Central  PubMed  Google Scholar 

  161. Keeling KM, Bedwell DM (2011) Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases. Wiley Interdiscip Rev RNA 2:837–852

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Yang C, Yang Y, Brennan L, Bouhassira EE, Kantorow M et al (2010) Efficient generation of lens progenitor cells and lentoid bodies from human embryonic stem cells in chemically defined conditions. FASEB J 24:3274–3283

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Qiu X, Yang J, Liu T, Jiang Y, Le Q et al (2012) Efficient generation of lens progenitor cells from cataract patient-specific induced pluripotent stem cells. PLoS One 7:e32612

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Kubo E, Hasanova N, Sasaki H, Singh DP (2013) Dynamic and differential regulation in the microRNA expression in the developing and mature cataractous rat lens. J Cell Mol Med 17:1146–1159

    CAS  PubMed  Google Scholar 

  165. Wang Y, Li W, Zang X, Chen N, Liu T et al (2013) MicroRNA-204-5p regulates epithelial-to-mesenchymal transition during human posterior capsule opacification by targeting SMAD4. Invest Ophthalmol Vis Sci 54:323–332

    PubMed  Google Scholar 

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Acknowledgements

This work was supported by NIH grants R01 EY012200 (AC), EY014237 (AC), and EY015518 (EVS) and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences.

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Authors and Affiliations

  1. The Departments Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Ales Cvekl & Ilana B. Friedman

  2. The Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

    Ales Cvekl

  3. Division of Developmental Biology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Elena V. Semina

  4. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Elena V. Semina

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  1. Ales Cvekl
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  2. Ilana B. Friedman
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  3. Elena V. Semina
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Correspondence to Ales Cvekl .

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Editors and Affiliations

  1. Department of Ophthalmology, Wakayama Medical University School of Medicine, Wakayama, Wakayama, Japan

    Shizuya Saika

  2. John A. Moran Eye Center University of Utah, Salt Lake City, Utah, USA

    Liliana Werner

  3. School of Medical Sciences Anatomy & Histology, Lens Research Laboratory The University of Sydney, Sydney, New South Wales, Australia

    Frank J. Lovicu

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Cvekl, A., Friedman, I.B., Semina, E.V. (2014). Lens-Specific Transcription Factors and Their Roles in Diagnosis and Treatment of Human Congenital Cataract. In: Saika, S., Werner, L., Lovicu, F. (eds) Lens Epithelium and Posterior Capsular Opacification. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54300-8_6

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