Vsx2 Controls Eye Organogenesis and Retinal Progenitor Identity Via Homeodomain and Non-Homeodomain Residues Required for High Affinity DNA Binding

English version České info

The homeodomain and adjacent CVC domain in the visual system homeobox (VSX) proteins are conserved from nematodes to humans. Humans with missense mutations in these regions of VSX2 have microphthalmia, suggesting both regions are critical for function. To assess this, we generated the corresponding mutations in mouse Vsx2. The homeodomain mutant protein lacked DNA binding activity and the knock-in mutant phenocopied the null mutant, ocular retardation J. The CVC mutant protein exhibited weakened DNA binding; and, although the corresponding knock-in allele was recessive, it unexpectedly caused the strongest phenotype, as indicated by severe microphthalmia and hyperpigmentation of the neural retina. This occurred through a cryptic transcriptional feedback loop involving the transcription factors Mitf and Otx1 and the Cdk inhibitor p27^Kip1. Our data suggest that the phenotypic severity of the CVC mutant depends on the weakened DNA binding activity elicited by the CVC mutation and a previously unknown protein interaction between Vsx2 and its regulatory target Mitf. Our data also suggest that an essential function of the CVC domain is to assist the homeodomain in high-affinity DNA binding, which is required for eye organogenesis and unhindered execution of the retinal progenitor program in mammals. Finally, the genetic and phenotypic behaviors of the CVC mutation suggest it has the characteristics of a recessive neomorph, a rare type of genetic allele.

Vyšlo v časopise: Vsx2 Controls Eye Organogenesis and Retinal Progenitor Identity Via Homeodomain and Non-Homeodomain Residues Required for High Affinity DNA Binding. PLoS Genet 8(9): e32767. doi:10.1371/journal.pgen.1002924
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002924

Souhrn

Zdroje

1. VaquerizasJM, KummerfeldSK, TeichmannSA, LuscombeNM (2009) A census of human transcription factors: function, expression and evolution. Nat Rev Genet 10: 252–263.

2. FraenkelE, PaboCO (1998) Comparison of X-ray and NMR structures for the Antennapedia homeodomain-DNA complex. Nat Struct Biol 5: 692–697.

3. ChiYI (2005) Homeodomain revisited: a lesson from disease-causing mutations. Hum Genet 116: 433–444.

4. AffolterM, SlatteryM, MannRS (2008) A lexicon for homeodomain-DNA recognition. Cell 133: 1133–1135.

5. BergerMF, BadisG, GehrkeAR, TalukderS, PhilippakisAA, et al. (2008) Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell 133: 1266–1276.

6. NoyesMB, ChristensenRG, WakabayashiA, StormoGD, BrodskyMH, et al. (2008) Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites. Cell 133: 1277–1289.

7. HollandPW, BoothHA, BrufordEA (2007) Classification and nomenclature of all human homeobox genes. BMC Biol 5: 47.

8. BachI, CarriereC, OstendorffHP, AndersenB, RosenfeldMG (1997) A family of LIM domain-associated cofactors confer transcriptional synergism between LIM and Otx homeodomain proteins. Genes Dev 11: 1370–1380.

9. PhillipsK, LuisiB (2000) The virtuoso of versatility: POU proteins that flex to fit. J Mol Biol 302: 1023–1039.

10. BurglinTR (2011) Homeodomain subtypes and functional diversity. Subcell Biochem 52: 95–122.

11. MannRS, LelliKM, JoshiR (2009) Hox specificity unique roles for cofactors and collaborators. Curr Top Dev Biol 88: 63–101.

12. PiperDE, BatchelorAH, ChangCP, ClearyML, WolbergerC (1999) Structure of a HoxB1-Pbx1 heterodimer bound to DNA: role of the hexapeptide and a fourth homeodomain helix in complex formation. Cell 96: 587–597.

13. FarberPJ, MittermaierA (2011) Concerted dynamics link allosteric sites in the PBX homeodomain. J Mol Biol 405: 819–830.

14. RohsR, JinX, WestSM, JoshiR, HonigB, et al. (2010) Origins of specificity in protein-DNA recognition. Annu Rev Biochem 79: 233–269.

15. SvendsenPC, McGheeJD (1995) The C. elegans neuronally expressed homeobox gene ceh-10 is closely related to genes expressed in the vertebrate eye. Development 121: 1253–1262.

16. LevineEM, HitchcockPF, GlasgowE, SchechterN (1994) Restricted expression of a new paired-class homeobox gene in normal and regenerating adult goldfish retina. J Comp Neurol 348: 596–606.

17. LiuIS, ChenJD, PloderL, VidgenD, van der KooyD, et al. (1994) Developmental expression of a novel murine homeobox gene (Chx10): evidence for roles in determination of the neuroretina and inner nuclear layer. Neuron 13: 377–393.

18. ForresterWC, PerensE, ZallenJA, GarrigaG (1998) Identification of Caenorhabditis elegans genes required for neuronal differentiation and migration. Genetics 148: 151–165.

19. Altun-GultekinZ, AndachiY, TsalikEL, PilgrimD, KoharaY, et al. (2001) A regulatory cascade of three homeobox genes, ceh-10, ttx-3 and ceh-23, controls cell fate specification of a defined interneuron class in C. elegans. Development 128: 1951–1969.

20. Bar-YosefU, AbuelaishI, HarelT, HendlerN, OfirR, et al. (2004) CHX10 mutations cause non-syndromic microphthalmia/anophthalmia in Arab and Jewish kindreds. Hum Genet 115: 302–309.

21. HeonE, GreenbergA, KoppKK, RootmanD, VincentAL, et al. (2002) VSX1: a gene for posterior polymorphous dystrophy and keratoconus. Hum Mol Genet 11: 1029–1036.

22. Mintz-HittnerHA, SeminaEV, FrishmanLJ, PragerTC, MurrayJC (2004) VSX1 (RINX) mutation with craniofacial anomalies, empty sella, corneal endothelial changes, and abnormal retinal and auditory bipolar cells. Ophthalmology 111: 828–836.

23. AungT, LimMC, WongTT, ThalamuthuA, YongVH, et al. (2008) Molecular analysis of CHX10 and MFRP in Chinese subjects with primary angle closure glaucoma and short axial length eyes. Mol Vis 14: 1313–1318.

24. IseriSU, WyattAW, NurnbergG, KluckC, NurnbergP, et al. (2010) Use of genome-wide SNP homozygosity mapping in small pedigrees to identify new mutations in VSX2 causing recessive microphthalmia and a semidominant inner retinal dystrophy. Hum Genet 128: 51–60.

25. ReisLM, KhanA, KariminejadA, EbadiF, TylerRC, et al. (2011) VSX2 mutations in autosomal recessive microphthalmia. Mol Vis 17: 2527–2532.

26. TanwarM, KumarM, NayakB, PathakD, SharmaN, et al. (2010) VSX1 gene analysis in keratoconus. Mol Vis 16: 2395–2401.

27. WatsonT, ChowRL (2011) Absence of Vsx1 expression in the normal and damaged mouse cornea. Mol Vis 17: 737–744.

28. Ferda PercinE, PloderLA, YuJJ, AriciK, HorsfordDJ, et al. (2000) Human microphthalmia associated with mutations in the retinal homeobox gene CHX10. Nat Genet 25: 397–401.

29. Faiyaz-Ul-HaqueM, ZaidiSH, Al-MureikhiMS, PeltekovaI, TsuiLC, et al. (2007) Mutations in the CHX10 gene in non-syndromic microphthalmia/anophthalmia patients from Qatar. Clin Genet 72: 164–166.

30. BurmeisterM, NovakJ, LiangMY, BasuS, PloderL, et al. (1996) Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nat Genet 12: 376–384.

31. BarabinoSM, SpadaF, CotelliF, BoncinelliE (1997) Inactivation of the zebrafish homologue of Chx10 by antisense oligonucleotides causes eye malformations similar to the ocular retardation phenotype. Mech Dev 63: 133–143.

32. ClarkAM, YunS, VeienES, WuYY, ChowRL, et al. (2008) Negative regulation of Vsx1 by its paralog Chx10/Vsx2 is conserved in the vertebrate retina. Brain Res 1192: 99–113.

33. VitorinoM, JusufPR, MaurusD, KimuraY, HigashijimaS, et al. (2009) Vsx2 in the zebrafish retina: restricted lineages through derepression. Neural Dev 4: 14.

34. DorvalKM, BobechkoBP, AhmadKF, BremnerR (2005) Transcriptional activity of the paired-like homeodomain proteins CHX10 and VSX1. J Biol Chem 280: 10100–10108.

35. KurtzmanAL, GregoriL, HaasAL, SchechterN (2000) Ubiquitination and degradation of the zebrafish paired-like homeobox protein VSX-1. J Neurochem 75: 48–55.

36. DorvalKM, BobechkoBP, FujiedaH, ChenS, ZackDJ, et al. (2006) CHX10 targets a subset of photoreceptor genes. J Biol Chem 281: 744–751.

37. ReichmanS, KalathurRK, LambardS, Ait-AliN, YangY, et al. (2010) The homeobox gene CHX10/VSX2 regulates RdCVF promoter activity in the inner retina. Hum Mol Genet 19: 250–261.

38. RowanS, CepkoCL (2005) A POU factor binding site upstream of the Chx10 homeobox gene is required for Chx10 expression in subsets of retinal progenitor cells and bipolar cells. Dev Biol 281: 240–255.

39. BhartiK, LiuW, CsermelyT, BertuzziS, ArnheiterH (2008) Alternative promoter use in eye development: the complex role and regulation of the transcription factor MITF. Development 135: 1169–1178.

40. RowanS, ChenCM, YoungTL, FisherDE, CepkoCL (2004) Transdifferentiation of the retina into pigmented cells in ocular retardation mice defines a new function of the homeodomain gene Chx10. Development 131: 5139–5152.

41. HorsfordDJ, NguyenMT, SellarGC, KotharyR, ArnheiterH, et al. (2005) Chx10 repression of Mitf is required for the maintenance of mammalian neuroretinal identity. Development 132: 177–187.

42. KonyukhovBV, SazhinaMV (1966) Interaction of the genes of ocular retardation and microphthalmia in mice. Folia Biol (Praha) 12: 116–123.

43. SteingrimssonE, CopelandNG, JenkinsNA (2004) Melanocytes and the Microphthalmia Transcription Factor Network. Annu Rev Genet 38: 365–411.

44. SaadiI, SeminaEV, AmendtBA, HarrisDJ, MurphyKP, et al. (2001) Identification of a dominant negative homeodomain mutation in Rieger syndrome. J Biol Chem 276: 23034–23041.

45. ChaneyBA, Clark-BaldwinK, DaveV, MaJ, RanceM (2005) Solution structure of the K50 class homeodomain PITX2 bound to DNA and implications for mutations that cause Rieger syndrome. Biochemistry 44: 7497–7511.

46. BuntingM, BernsteinKE, GreerJM, CapecchiMR, ThomasKR (1999) Targeting genes for self-excision in the germ line. Genes Dev 13: 1524–1528.

47. Bone-LarsonC, BasuS, RadelJD, LiangM, PerozekT, et al. (2000) Partial rescue of the ocular retardation phenotype by genetic modifiers. J Neurobiol 42: 232–247.

48. WongG, CongerSB, BurmeisterM (2006) Mapping of genetic modifiers affecting the eye phenotype of ocular retardation (Chx10or-J) mice. Mamm Genome 17: 518–525.

49. DhomenNS, BalagganKS, PearsonRA, BainbridgeJW, LevineEM, et al. (2006) Absence of chx10 causes neural progenitors to persist in the adult retina. Invest Ophthalmol Vis Sci 47: 386–396.

50. GreenES, StubbsJL, LevineEM (2003) Genetic rescue of cell number in a mouse model of microphthalmia: interactions between Chx10 and G1-phase cell cycle regulators. Development 130: 539–552.

51. Livne-BarI, PacalM, CheungMC, HankinM, TrogadisJ, et al. (2006) Chx10 is required to block photoreceptor differentiation but is dispensable for progenitor proliferation in the postnatal retina. Proc Natl Acad Sci U S A 103: 4988–4993.

52. SigulinskyCL, GreenES, ClarkAM, LevineEM (2008) Vsx2/Chx10 ensures the correct timing and magnitude of Hedgehog signaling in the mouse retina. Dev Biol 317: 560–575.

53. KonyukhovBV, SazhinaMV (1971) Genetic control over the duration of G 1 phase. Experientia 27: 970–971.

54. YunS, SaijohY, HirokawaKE, KopinkeD, MurtaughLC, et al. (2009) Lhx2 links the intrinsic and extrinsic factors that control optic cup formation. Development 136: 3895–3906.

55. NguyenM, ArnheiterH (2000) Signaling and transcriptional regulation in early mammalian eye development: a link between FGF and MITF. Development 127: 3581–3591.

56. BoraN, ConwaySJ, LiangH, SmithSB (1998) Transient overexpression of the Microphthalmia gene in the eyes of Microphthalmia vitiligo mutant mice. Dev Dyn 213: 283–292.

57. Martinez-MoralesJR, RodrigoI, BovolentaP (2004) Eye development: a view from the retina pigmented epithelium. Bioessays 26: 766–777.

58. WestenskowPD, McKeanJB, KuboF, NakagawaS, FuhrmannS (2010) Ectopic Mitf in the embryonic chick retina by co-transfection of beta-catenin and Otx2. Invest Ophthalmol Vis Sci 51: 5328–5335.

59. Martinez-MoralesJR, SignoreM, AcamporaD, SimeoneA, BovolentaP (2001) Otx genes are required for tissue specification in the developing eye. Development 128: 2019–2030.

60. Martinez-MoralesJR, DolezV, RodrigoI, ZaccariniR, LeconteL, et al. (2003) OTX2 activates the molecular network underlying retina pigment epithelium differentiation. The Journal of biological chemistry 278: 21721–21731.

61. DasG, ChoiY, SicinskiP, LevineEM (2009) Cyclin D1 fine-tunes the neurogenic output of embryonic retinal progenitor cells. Neural Dev 4: 15.

62. EvansAL, GagePJ (2005) Expression of the homeobox gene Pitx2 in neural crest is required for optic stalk and ocular anterior segment development. Hum Mol Genet 14: 3347–3359.

63. GagePJ, RhoadesW, PruckaSK, HjaltT (2005) Fate maps of neural crest and mesoderm in the mammalian eye. Invest Ophthalmol Vis Sci 46: 4200–4208.

64. HjaltTA, SeminaEV, AmendtBA, MurrayJC (2000) The Pitx2 protein in mouse development. Dev Dyn 218: 195–200.

65. FuhrmannS, LevineEM, RehTA (2000) Extraocular mesenchyme patterns the optic vesicle during early eye development in the embryonic chick. Development 127: 4599–4609.

66. HodgkinsonCA, MooreKJ, NakayamaA, SteingrimssonE, CopelandNG, et al. (1993) Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell 74: 395–404.

67. HemesathTJ, SteingrimssonE, McGillG, HansenMJ, VaughtJ, et al. (1994) microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Genes Dev 8: 2770–2780.

68. ScholtzCL, ChanKK (1987) Complicated colobomatous microphthalmia in the microphthalmic (mi/mi) mouse. Development 99: 501–508.

69. TsukijiN, NishiharaD, YajimaI, TakedaK, ShibaharaS, et al. (2009) Mitf functions as an in ovo regulator for cell differentiation and proliferation during development of the chick RPE. Dev Biol 326: 335–346.

70. LaughonA (1991) DNA binding specificity of homeodomains. Biochemistry 30: 11357–11367.

71. HanesSD, BrentR (1991) A genetic model for interaction of the homeodomain recognition helix with DNA. Science 251: 426–430.

72. FuhrmannS (2010) Eye morphogenesis and patterning of the optic vesicle. Current topics in developmental biology 93: 61–84.

73. MullerHJ (1932) Further Studies on the Nature and Causes of Gene Mutations. Proc Int Congr Genet 6: 213–252.

74. SijacicP, WangW, LiuZ (2011) Recessive antimorphic alleles overcome functionally redundant loci to reveal TSO1 function in Arabidopsis flowers and meristems. PLoS Genet 7: e1002352 doi:10.1371/journal.pgen.1002352.

75. MiskiminsR, SrinivasanR, Marin-HusstegeM, MiskiminsWK, Casaccia-BonnefilP (2002) p27(Kip1) enhances myelin basic protein gene promoter activity. J Neurosci Res 67: 100–105.

76. WeiQ, MiskiminsWK, MiskiminsR (2003) The Sp1 family of transcription factors is involved in p27(Kip1)-mediated activation of myelin basic protein gene expression. Mol Cell Biol 23: 4035–4045.

77. NguyenL, BessonA, HengJI, SchuurmansC, TeboulL, et al. (2006) p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex. Genes Dev 20: 1511–1524.

78. BienvenuF, JirawatnotaiS, EliasJE, MeyerCA, MizerackaK, et al. (2010) Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen. Nature 463: 374–378.

79. TongW, PollardJW (2001) Genetic evidence for the interactions of cyclin D1 and p27(Kip1) in mice. Mol Cell Biol 21: 1319–1328.

80. GengY, YuQ, SicinskaE, DasM, BronsonRT, et al. (2001) Deletion of the p27Kip1 gene restores normal development in cyclin D1-deficient mice. Proc Natl Acad Sci U S A 98: 194–199.

81. DyerMA, CepkoCL (2001) p27Kip1 and p57Kip2 regulate proliferation in distinct retinal progenitor cell populations. J Neurosci 21: 4259–4271.

82. LevineEM, CloseJ, FeroM, OstrovskyA, RehTA (2000) p27(Kip1) regulates cell cycle withdrawal of late multipotent progenitor cells in the mammalian retina. Dev Biol 219: 299–314.

83. CunninghamJJ, LevineEM, ZindyF, GoloubevaO, RousselMF, et al. (2002) The cyclin-dependent kinase inhibitors p19(Ink4d) and p27(Kip1) are coexpressed in select retinal cells and act cooperatively to control cell cycle exit. Mol Cell Neurosci 19: 359–374.

84. DasG, ClarkAM, LevineEM (2012) Cyclin D1 inactivation extends proliferation and alters histogenesis in the postnatal mouse retina. Developmental dynamics : an official publication of the American Association of Anatomists 241: 941–952.

85. CaiZ, FengGS, ZhangX (2010) Temporal requirement of the protein tyrosine phosphatase Shp2 in establishing the neuronal fate in early retinal development. J Neurosci 30: 4110–4119.

86. MorcilloJ, Martinez-MoralesJR, TrousseF, FerminY, SowdenJC, et al. (2006) Proper patterning of the optic fissure requires the sequential activity of BMP7 and SHH. Development 133: 3179–3190.

87. LevineEM, RoelinkH, TurnerJ, RehTA (1997) Sonic hedgehog promotes rod photoreceptor differentiation in mammalian retinal cells in vitro. J Neurosci 17: 6277–6288.

88. CapecchiMR (1980) High efficiency transformation by direct microinjection of DNA into cultured mammalian cells. Cell 22: 479–488.