Foxe3

Summary

Gene Symbol: Foxe3
Description: forkhead box E3
Alias: FREAC8, dyl, rct, forkhead box protein E3, Rinshoken cataract, dysgenetic lens
Species: mouse
Products:     Foxe3

Top Publications

  1. Sanyal S, Hawkins R. Dysgenetic lens (dyl)--a new gene in the mouse. Invest Ophthalmol Vis Sci. 1979;18:642-5 pubmed
    A new autosomal recessive gene, dysgenetic lens (dyl), in the mouse is described...
  2. Yoshimoto A, Saigou Y, Higashi Y, Kondoh H. Regulation of ocular lens development by Smad-interacting protein 1 involving Foxe3 activation. Development. 2005;132:4437-48 pubmed
    ..The persistence of the lens stalk resembles a defect in Foxe3 mutant mice, and Sip1-defective lenses lose Foxe3 expression, placing Foxe3 downstream of Sip1...
  3. Ormestad M, Blixt A, Churchill A, Martinsson T, Enerback S, Carlsson P. Foxe3 haploinsufficiency in mice: a model for Peters' anomaly. Invest Ophthalmol Vis Sci. 2002;43:1350-7 pubmed
    To evaluate the importance in anterior segment dysgenesis of genetic variation in Foxe3, a gene encoding a forkhead transcription factor specifically expressed in the lens.
  4. Rowan S, Siggers T, Lachke S, Yue Y, Bulyk M, Maas R. Precise temporal control of the eye regulatory gene Pax6 via enhancer-binding site affinity. Genes Dev. 2010;24:980-5 pubmed publisher
    ..Finally, we describe a mechanism whereby Pax6 levels are determined by transcriptional synergy of Prep1 bound to the two sites, while timing of enhancer activation is determined by binding site affinity. ..
  5. Garcia C, Huang J, Madakashira B, Liu Y, Rajagopal R, Dattilo L, et al. The function of FGF signaling in the lens placode. Dev Biol. 2011;351:176-85 pubmed publisher
    ..were present at normal levels in the remaining placode cells, including the transcription factors Pax6, Sox2 and FoxE3 and the lens-preferred protein ?A-crystallin...
  6. Blixt A, Mahlapuu M, Aitola M, Pelto Huikko M, Enerback S, Carlsson P. A forkhead gene, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle. Genes Dev. 2000;14:245-54 pubmed
    In the mouse mutant dysgenetic lens (dyl) the lens vesicle fails to separate from the ectoderm, causing a fusion between the lens and the cornea...
  7. Liu W, Lagutin O, Mende M, Streit A, Oliver G. Six3 activation of Pax6 expression is essential for mammalian lens induction and specification. EMBO J. 2006;25:5383-95 pubmed
    ..We conclude that Six3 directly activates Pax6 and probably also Sox2 in the PLE and regulates cell autonomously the earliest stages of mammalian lens induction. ..
  8. Le T, Conley K, Mead T, Rowan S, Yutzey K, Brown N. Requirements for Jag1-Rbpj mediated Notch signaling during early mouse lens development. Dev Dyn. 2012;241:493-504 pubmed publisher
    ..In addition, AP2?-Cre-mediated deletion of Rbpj resulted in embryos with cardiac outflow tract and liver deformities, and perinatal lethality. ..
  9. Faber S, Dimanlig P, Makarenkova H, Shirke S, Ko K, Lang R. Fgf receptor signaling plays a role in lens induction. Development. 2001;128:4425-38 pubmed
    ..5 but in addition, showed reduced levels of expression for Pax6, Sox2 and Foxe3, all markers of lens induction; (3) by performing crosses between Tfr7 transgenic and Bmp7-null mice, we showed ..
  10. Blixt A, Landgren H, Johansson B, Carlsson P. Foxe3 is required for morphogenesis and differentiation of the anterior segment of the eye and is sensitive to Pax6 gene dosage. Dev Biol. 2007;302:218-29 pubmed
    The dysgenetic lens (dyl) mouse mutant has mutations in Foxe3, which inactivate DNA binding by the encoded forkhead transcription factor...

Detail Information

Publications55

  1. Sanyal S, Hawkins R. Dysgenetic lens (dyl)--a new gene in the mouse. Invest Ophthalmol Vis Sci. 1979;18:642-5 pubmed
    A new autosomal recessive gene, dysgenetic lens (dyl), in the mouse is described...
  2. Yoshimoto A, Saigou Y, Higashi Y, Kondoh H. Regulation of ocular lens development by Smad-interacting protein 1 involving Foxe3 activation. Development. 2005;132:4437-48 pubmed
    ..The persistence of the lens stalk resembles a defect in Foxe3 mutant mice, and Sip1-defective lenses lose Foxe3 expression, placing Foxe3 downstream of Sip1...
  3. Ormestad M, Blixt A, Churchill A, Martinsson T, Enerback S, Carlsson P. Foxe3 haploinsufficiency in mice: a model for Peters' anomaly. Invest Ophthalmol Vis Sci. 2002;43:1350-7 pubmed
    To evaluate the importance in anterior segment dysgenesis of genetic variation in Foxe3, a gene encoding a forkhead transcription factor specifically expressed in the lens.
  4. Rowan S, Siggers T, Lachke S, Yue Y, Bulyk M, Maas R. Precise temporal control of the eye regulatory gene Pax6 via enhancer-binding site affinity. Genes Dev. 2010;24:980-5 pubmed publisher
    ..Finally, we describe a mechanism whereby Pax6 levels are determined by transcriptional synergy of Prep1 bound to the two sites, while timing of enhancer activation is determined by binding site affinity. ..
  5. Garcia C, Huang J, Madakashira B, Liu Y, Rajagopal R, Dattilo L, et al. The function of FGF signaling in the lens placode. Dev Biol. 2011;351:176-85 pubmed publisher
    ..were present at normal levels in the remaining placode cells, including the transcription factors Pax6, Sox2 and FoxE3 and the lens-preferred protein ?A-crystallin...
  6. Blixt A, Mahlapuu M, Aitola M, Pelto Huikko M, Enerback S, Carlsson P. A forkhead gene, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle. Genes Dev. 2000;14:245-54 pubmed
    In the mouse mutant dysgenetic lens (dyl) the lens vesicle fails to separate from the ectoderm, causing a fusion between the lens and the cornea...
  7. Liu W, Lagutin O, Mende M, Streit A, Oliver G. Six3 activation of Pax6 expression is essential for mammalian lens induction and specification. EMBO J. 2006;25:5383-95 pubmed
    ..We conclude that Six3 directly activates Pax6 and probably also Sox2 in the PLE and regulates cell autonomously the earliest stages of mammalian lens induction. ..
  8. Le T, Conley K, Mead T, Rowan S, Yutzey K, Brown N. Requirements for Jag1-Rbpj mediated Notch signaling during early mouse lens development. Dev Dyn. 2012;241:493-504 pubmed publisher
    ..In addition, AP2?-Cre-mediated deletion of Rbpj resulted in embryos with cardiac outflow tract and liver deformities, and perinatal lethality. ..
  9. Faber S, Dimanlig P, Makarenkova H, Shirke S, Ko K, Lang R. Fgf receptor signaling plays a role in lens induction. Development. 2001;128:4425-38 pubmed
    ..5 but in addition, showed reduced levels of expression for Pax6, Sox2 and Foxe3, all markers of lens induction; (3) by performing crosses between Tfr7 transgenic and Bmp7-null mice, we showed ..
  10. Blixt A, Landgren H, Johansson B, Carlsson P. Foxe3 is required for morphogenesis and differentiation of the anterior segment of the eye and is sensitive to Pax6 gene dosage. Dev Biol. 2007;302:218-29 pubmed
    The dysgenetic lens (dyl) mouse mutant has mutations in Foxe3, which inactivate DNA binding by the encoded forkhead transcription factor...
  11. Medina Martinez O, Brownell I, Amaya Manzanares F, Hu Q, Behringer R, Jamrich M. Severe defects in proliferation and differentiation of lens cells in Foxe3 null mice. Mol Cell Biol. 2005;25:8854-63 pubmed
    ..b>Foxe3 encodes a winged helix-forkhead transcription factor that is initially expressed in the developing brain and in ..
  12. Zhao H, Yang T, Madakashira B, Thiels C, Bechtle C, Garcia C, et al. Fibroblast growth factor receptor signaling is essential for lens fiber cell differentiation. Dev Biol. 2008;318:276-88 pubmed publisher
    ..Therefore, while signaling by FGF receptors is essential for lens fiber differentiation, different FGF receptors function redundantly. ..
  13. Yamada R, Mizutani Koseki Y, Hasegawa T, Osumi N, Koseki H, Takahashi N. Cell-autonomous involvement of Mab21l1 is essential for lens placode development. Development. 2003;130:1759-70 pubmed
    ..The defects in lens placode development correlate with delayed and insufficient expression of Foxe3, which is also required for lens development, while Maf, Sox2, Six3 and PAX6 levels are not significantly affected...
  14. Medina Martinez O, Shah R, Jamrich M. Pitx3 controls multiple aspects of lens development. Dev Dyn. 2009;238:2193-201 pubmed publisher
    ..The genetic interactions between Pitx3 and Foxe3 were investigated, as these two transcription factors are expressed at the same time in lens development and their ..
  15. Wiley L, Dattilo L, Kang K, Giovannini M, Beebe D. The tumor suppressor merlin is required for cell cycle exit, terminal differentiation, and cell polarity in the developing murine lens. Invest Ophthalmol Vis Sci. 2010;51:3611-8 pubmed publisher
    ..cells lacking Nf2 did not fully exit the cell cycle and continued to express epithelial cell markers, such as FoxE3 and E-cadherin, despite expressing the fiber cell marker Prox1. Many fiber cells lost their elongated morphology...
  16. Kerr C, Huang J, Williams T, West Mays J. Activation of the hedgehog signaling pathway in the developing lens stimulates ectopic FoxE3 expression and disruption in fiber cell differentiation. Invest Ophthalmol Vis Sci. 2012;53:3316-30 pubmed publisher
    ..Altered lens morphology correlated with ectopic expression of FoxE3, which encodes a critical gene required for human and mouse lens development...
  17. Ahmad N, Aslam M, Muenster D, Horsch M, Khan M, Carlsson P, et al. Pitx3 directly regulates Foxe3 during early lens development. Int J Dev Biol. 2013;57:741-51 pubmed publisher
    ..This was associated with loss of Foxe3 expression, complete absence of Prox1 expression, reduced expression of epsilon-tubulin and earlier expression of ..
  18. Wada K, Saito J, Yamaguchi M, Seki Y, Furugori M, Takahashi G, et al. Pde6brd1 mutation modifies cataractogenesis in Foxe3rct mice. Biochem Biophys Res Commun. 2018;496:231-237 pubmed publisher
    The Foxe3rct mutation, which causes early-onset cataracts, is a recessive mutation found in SJL/J mice...
  19. Landgren H, Blixt A, Carlsson P. Persistent FoxE3 expression blocks cytoskeletal remodeling and organelle degradation during lens fiber differentiation. Invest Ophthalmol Vis Sci. 2008;49:4269-77 pubmed publisher
    ..b>Foxe3, a forkhead transcription factor, is essential for proliferation and survival of the epithelial cells, and ..
  20. Cavalheiro G, Matos Rodrigues G, Gomes A, Rodrigues P, Martins R. c-Myc regulates cell proliferation during lens development. PLoS ONE. 2014;9:e87182 pubmed publisher
    ..Interestingly, a sharp decrease in the expression of the forkhead box transcription factor Foxe3 was also observed following c-myc inactivation...
  21. Antosova B, Smolikova J, Klimova L, Lachova J, Bendova M, Kozmikova I, et al. The Gene Regulatory Network of Lens Induction Is Wired through Meis-Dependent Shadow Enhancers of Pax6. PLoS Genet. 2016;12:e1006441 pubmed publisher
    ..Moreover, they reveal an apparent robustness in the gene regulatory mechanism whereby two independent "shadow enhancers" maintain critical levels of a dosage-sensitive gene, Pax6, during lens induction. ..
  22. Wolf L, Harrison W, Huang J, Xie Q, Xiao N, Sun J, et al. Histone posttranslational modifications and cell fate determination: lens induction requires the lysine acetyltransferases CBP and p300. Nucleic Acids Res. 2013;41:10199-214 pubmed publisher
  23. Semina E, Brownell I, Mintz Hittner H, Murray J, Jamrich M. Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum Mol Genet. 2001;10:231-6 pubmed
    ..The recently described forkhead transcription factor gene Foxe3 was shown to be involved in the dysgenetic lens phenotype in mice, which is characterized by small cataractic lens and anterior segment anomalies...
  24. He S, Limi S, McGreal R, Xie Q, Brennan L, Kantorow W, et al. Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation. Development. 2016;143:1937-47 pubmed publisher
  25. Jänne P, Rochelle J, Martin DeLeon P, Stambolian D, Seldin M, Nussbaum R. Mapping of the 75-kDa inositol polyphosphate-5-phosphatase (Inpp5b) to distal mouse chromosome 4 and its exclusion as a candidate gene for dysgenetic lens. Genomics. 1995;28:280-5 pubmed
    ..The position of Inpp5b on mouse Chromosome 4 is in the vicinity of the mouse developmental mutation dysgenetic lens (dyl). However, using a genetic approach, we show that Inpp5b maps distal to dyl on mouse Chromosome 4.
  26. Sanyal S, Van Nie R, de Moes J, Hawkins R. Map position of dysgenetic lens (dyl) locus on chromosome 4 in the mouse. Genet Res. 1986;48:199-200 pubmed
  27. Zhao J, Kawai K, Wang H, Wu D, Wang M, Yue Z, et al. Loss of Msx2 function down-regulates the FoxE3 expression and results in anterior segment dysgenesis resembling Peters anomaly. Am J Pathol. 2012;180:2230-9 pubmed publisher
    ..Loss of Msx2 down-regulated FoxE3 expression and up-regulated Prox1 and crystallin expression in the lens...
  28. Goudreau G, Petrou P, Reneker L, Graw J, Löster J, Gruss P. Mutually regulated expression of Pax6 and Six3 and its implications for the Pax6 haploinsufficient lens phenotype. Proc Natl Acad Sci U S A. 2002;99:8719-24 pubmed
    ..Our findings thus provide a mechanism implicating gene regulatory interactions between Pax6 and Six3 in the tissue-specific defects found in Pax6 heterozygous mice. ..
  29. Ho H, Chang K, Nichols J, Li M. Homeodomain protein Pitx3 maintains the mitotic activity of lens epithelial cells. Mech Dev. 2009;126:18-29 pubmed publisher
    ..These defects are at least partially attributed to the loss of FoxE3 and misexpression of Prox1 in the lens vesicle epithelial cells...
  30. Dash S, Dang C, Beebe D, Lachke S. Deficiency of the RNA binding protein caprin2 causes lens defects and features of Peters anomaly. Dev Dyn. 2015;244:1313-27 pubmed publisher
    ..These data suggest that a conserved RBP Caprin2 functions in distinct morphological events in mammalian eye development. ..
  31. Wada K, Maeda Y, Watanabe K, Oshio T, Ueda T, Takahashi G, et al. A deletion in a cis element of Foxe3 causes cataracts and microphthalmia in rct mice. Mamm Genome. 2011;22:693-702 pubmed publisher
    The Rinshoken cataract (rct) mutation, which causes congenital cataracts, is a recessive mutation found in SJL/J mice. All mutants present with opacity in the lens by 2 months of age. The rct locus was mapped to a 1...
  32. Wiley L, Rajagopal R, Dattilo L, Beebe D. The tumor suppressor gene Trp53 protects the mouse lens against posterior subcapsular cataracts and the BMP receptor Acvr1 acts as a tumor suppressor in the lens. Dis Model Mech. 2011;4:484-95 pubmed publisher
    ..Acvr1 acts as a tumor suppressor in the lens. Enhancing p53 function in the lens could contribute to the prevention of steroid- and radiation-induced posterior subcapsular cataracts. ..
  33. Kuang S, Medina Martinez O, Guo D, Gong L, Regalado E, Reynolds C, et al. FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. J Clin Invest. 2016;126:948-61 pubmed publisher
    ..Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD...
  34. Khan S, Vasanth S, Kabir F, Gottsch J, Khan A, Chaerkady R, et al. FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nat Commun. 2016;7:10953 pubmed publisher
    b>FOXE3 is a lens-specific transcription factor that has been associated with anterior segment ocular dysgenesis...
  35. Wolf N, Galecki A, Lipman R, Chen S, Smith Wheelock M, Burke D, et al. Quantitative trait locus mapping for age-related cataract severity and synechia prevalence using four-way cross mice. Invest Ophthalmol Vis Sci. 2004;45:1922-9 pubmed
    ..The results provide a first step toward identification of the individual genes involved and may help to guide the search for homologous human genes. ..
  36. MATTESON P, Desai J, Korstanje R, Lazar G, Borsuk T, Rollins J, et al. The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development. Proc Natl Acad Sci U S A. 2008;105:2088-93 pubmed publisher
    ..Bioinformatic, sequence, genetic, and functional data have determined that Foxe3, a key regulator of lens development, is a gene responsible for the vl cataract-modifying phenotype...
  37. Dimanlig P, Faber S, Auerbach W, Makarenkova H, Lang R. The upstream ectoderm enhancer in Pax6 has an important role in lens induction. Development. 2001;128:4415-24 pubmed
    ..of the ectoderm enhancer causes loss of expression of Foxe3, a transcription factor gene mutated in the dysgenetic lens mouse...
  38. Manthey A, Lachke S, FitzGerald P, Mason R, Scheiblin D, McDonald J, et al. Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development. Mech Dev. 2014;131:86-110 pubmed publisher
  39. Huang J, Liu Y, Oltean A, Beebe D. Bmp4 from the optic vesicle specifies murine retina formation. Dev Biol. 2015;402:119-26 pubmed publisher
    ..Differences in the signaling pathways required for specification of the retina and retinal pigmented epithelium in chicken and mouse embryos suggest major changes in signaling during the evolution of the vertebrate eye. ..
  40. Swindell E, Liu C, Shah R, Smith A, Lang R, Jamrich M. Eye formation in the absence of retina. Dev Biol. 2008;322:56-64 pubmed publisher
    ..One involved in the formation of the eyeball and the second involved in the formation of the auxiliary eye structures. ..
  41. Pathania M, Wang Y, Simirskii V, Duncan M. β1-integrin controls cell fate specification in early lens development. Differentiation. 2016;92:133-147 pubmed publisher
    ..Thus, β1-integrin has an important role in fine-tuning the response of the early lens to the gradient of growth factors that regulate lens fiber cell differentiation. ..
  42. Yan X, Sabrautzki S, Horsch M, Fuchs H, Gailus Durner V, Beckers J, et al. Peroxidasin is essential for eye development in the mouse. Hum Mol Genet. 2014;23:5597-614 pubmed publisher
    ..of the lens is disrupted in association with aberrant expression of transcription factor genes (Pax6 and Foxe3) in mutant eyes...
  43. Brahma S, Sanyal S. Immunohistochemical studies of lens crystallins in the dysgenetic lens (dyl) mutant mice. Exp Eye Res. 1984;38:305-11 pubmed
    The lens in the dyl mutant mice shows a persistent lens-ectodermal connection as well as degeneration and extrusion of lens materials after the initial differentiation of the fibres...
  44. Choi J, Ting C, Trogrlic L, Milevski S, Familari M, Martinez G, et al. A role for smoothened during murine lens and cornea development. PLoS ONE. 2014;9:e108037 pubmed publisher
    ..lenses were smaller and showed normal expression of p57Kip2, c-Maf, E-cadherin and Pax6, reduced expression of FoxE3 and Ptch1 and decreased nuclear Hes1. There was normal G1-S phase but decreased G2-M phase transition at E16...
  45. Yamada R, Mizutani Koseki Y, Koseki H, Takahashi N. Requirement for Mab21l2 during development of murine retina and ventral body wall. Dev Biol. 2004;274:295-307 pubmed
    ..Our results reveal that Mab21l2 plays crucial roles in retina and in ventral body wall formation. ..
  46. Wang Y, Li W, Wang Y, Huang Y. Growth inhibition of human lens epithelial cells by short hairpin RNA in transcription factor forkhead box E3 (FOXE3). Graefes Arch Clin Exp Ophthalmol. 2012;250:999-1007 pubmed publisher
    ..to investigate whether small hairpin RNA (shRNA)-mediated gene silencing of transcription factor forkhead box E3 (FOXE3) can be employed to inhibit the expression of FOXE3 and suppress the growth in lens epithelial cells...
  47. Maeda Y, Funata N, Takahama S, Sugata Y, Yonekawa H. Two interactive genes responsible for a new inherited cataract (RCT) in the mouse. Mamm Genome. 2001;12:278-83 pubmed
    We discovered a mutant mouse, RCT (Rinshoken cataract), with a new congenital cataract in strain SJL/J. The opacity of the lens associated with microphthalmia could be observed visually at 3 to 3.5 months of age...
  48. Rajagopal R, Huang J, Dattilo L, Kaartinen V, Mishina Y, Deng C, et al. The type I BMP receptors, Bmpr1a and Acvr1, activate multiple signaling pathways to regulate lens formation. Dev Biol. 2009;335:305-16 pubmed publisher
    ..Lens formation, placode cell proliferation, the expression of FoxE3, a lens-specific transcription factor, and the lens protein, alphaA-crystallin were regulated by BMP receptors in ..
  49. Zhao H, Yang Y, Partanen J, Ciruna B, Rossant J, Robinson M. Fibroblast growth factor receptor 1 (Fgfr1) is not essential for lens fiber differentiation in mice. Mol Vis. 2006;12:15-25 pubmed
    ..Overall, our results demonstrate that Fgfr1 is not cell autonomously essential for lens development and suggests functional redundancy among different FGF receptor genes with respect to lens fiber differentiation. ..
  50. Carbe C, Garg A, Cai Z, Li H, Powers A, Zhang X. An allelic series at the paired box gene 6 (Pax6) locus reveals the functional specificity of Pax genes. J Biol Chem. 2013;288:12130-41 pubmed publisher
    ..Our results show that Pax6 is uniquely required for eye development, but in brain development, Pax6 can be functionally substituted by related Pax family genes that share a similar paired domain binding specificity. ..
  51. Brownell I, Dirksen M, Jamrich M. Forkhead Foxe3 maps to the dysgenetic lens locus and is critical in lens development and differentiation. Genesis. 2000;27:81-93 pubmed
    ..Foxe3 maps to a chromosomal region containing the dysgenetic lens (dyl) mutation. Mice homozygous for dyl display several defects in lens development...
  52. Islam L, Kelberman D, Williamson L, Lewis N, Glindzicz M, Nischal K, et al. Functional analysis of FOXE3 mutations causing dominant and recessive ocular anterior segment disease. Hum Mutat. 2015;36:296-300 pubmed publisher
    Mutations in FOXE3 are associated with both recessive and dominant inheritance of severe anterior ocular malformations and glaucoma. However, functional analyses of putative pathogenic mutations have not been performed...
  53. Maeda A, Moriguchi T, Hamada M, Kusakabe M, Fujioka Y, Nakano T, et al. Transcription factor GATA-3 is essential for lens development. Dev Dyn. 2009;238:2280-91 pubmed publisher
    ..Thus, these observations suggest that GATA-3 is essential for lens cells differentiation and proper cell cycle control. ..
  54. Burns C, Zhang J, Brown E, Van Bibber A, van Es J, Clevers H, et al. Investigation of Frizzled-5 during embryonic neural development in mouse. Dev Dyn. 2008;237:1614-26 pubmed publisher
    ..Thus, the function of Fzd5 during eye development appears to be species-dependent. ..
  55. Pontoriero G, Deschamps P, Ashery Padan R, Wong R, Yang Y, Zavadil J, et al. Cell autonomous roles for AP-2alpha in lens vesicle separation and maintenance of the lens epithelial cell phenotype. Dev Dyn. 2008;237:602-17 pubmed publisher
    ..Expression of known regulators of lens vesicle separation, including Pax6, Pitx3, and Foxe3 was observed in the Le-AP-2alpha mutant lens demonstrating that these genes do not lie directly downstream of AP-..