Sox11 Is Required to Maintain Proper Levels of Hedgehog Signaling during Vertebrate Ocular Morphogenesis

English version České info

Ocular coloboma is a condition in which tissue is missing from a portion of the eye due to its abnormal development. Coloboma is also frequently associated with additional anomalies, including microphthalmia (abnormally small eye) and cataracts. Although some of the genes that cause coloboma have been identified, in the majority of cases the underlying genetic cause has not been determined. One pathway that has been implicated in coloboma is the Hedgehog (Hh) signaling pathway. In this study, we have taken advantage of the ability to titrate levels of gene expression in zebrafish to demonstrate for the first time that the transcription factor Sox11 is required to limit levels of Hedgehog (Hh) signaling during ocular development. We show that in the absence of Sox11, levels of the Sonic Hedgehog (Shh) ligand are greatly elevated, which disrupts the proper patterning of the optic stalk and optic vesicle, resulting in coloboma. We also provide evidence that SOX11 dosage changes or mutations contribute to human coloboma, microphthalmia, and rod photoreceptor dysfunction. Thus, our work establishes a novel link between Sox11 and Hh signaling, and suggests that mutations in SOX11 contribute to pediatric eye disorders such as coloboma.

Vyšlo v časopise: Sox11 Is Required to Maintain Proper Levels of Hedgehog Signaling during Vertebrate Ocular Morphogenesis. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004491
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004491

Souhrn

Zdroje

1. ShahSP, TaylorAE, SowdenJC, RaggeN, Russell-EggittI, et al. (2012) Anophthalmos, Microphthalmos, and Coloboma in the United Kingdom: Clinical Features, Results of Investigations, and Early Management. Ophthalmology 119 : 362–368.

2. ChangL, BlainD, BertuzziS, BrooksBP (2006) Uveal coloboma: clinical and basic science update. Current Opinion in Ophthalmology 17 : 447–470 410.1097/1001.icu.0000243020.0000282380.f0000243026

3. AmatoMA, BoyS, PerronM (2004) Hedgehog signaling in vertebrate eye development: a growing puzzle. Cellular and Molecular Life Sciences CMLS 61 : 899–910.

4. EkkerSC, UngarAR, GreensteinP, von KesslerDP, PorterJA, et al. (1995) Patterning activities of vertebrate hedgehog proteins in the developing eye and brain. Current Biology 5 : 944–955.

5. ZhangX-M, YangX-J (2001) Temporal and Spatial Effects of Sonic Hedgehog Signaling in Chick Eye Morphogenesis. Developmental Biology 233 : 271–290.

6. BakraniaP, Ugur IseriSA, WyattAW, BunyanDJ, LamWWK, et al. (2010) Sonic hedgehog mutations are an uncommon cause of developmental eye anomalies. American Journal of Medical Genetics Part A 152A: 1310–1313.

7. SanyanusinP, SchimmentiLA, McNoeLA, WardTA, PierpontME, et al. (1995) Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nature genetics 9 : 358–364.

8. SchimmentiLA, de la CruzJ, LewisRA, KarkeraJD, ManligasGS, et al. (2003) Novel mutation in sonic hedgehog in non-syndromic colobomatous microphthalmia. American Journal of Medical Genetics Part A 116A: 215–221.

9. SlavotinekAM, ChaoR, VacikT, YahyaviM, AbouzeidH, et al. (2012) VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: The first description of a VAX1 phenotype in humans. Human mutation 33 : 364–368.

10. Penzo-MéndezAI (2010) Critical roles for SoxC transcription factors in development and cancer. The International Journal of Biochemistry & Cell Biology 42 : 425–428.

11. de BontJM, KrosJM, PassierMM, ReddingiusRE, Sillevis SmittPA, et al. (2008) Differential expression and prognostic significance of SOX genes in pediatric medulloblastoma and ependymoma identified by microarray analysis. Neuro-oncology 10 : 648–660.

12. SockE, RettigSD, EnderichJ, BöslMR, TammER, et al. (2004) Gene Targeting Reveals a Widespread Role for the High-Mobility-Group Transcription Factor Sox11 in Tissue Remodeling. Molecular and cellular biology 24 : 6635–6644.

13. WurmA, SockE, FuchshoferR, WegnerM, TammER (2008) Anterior segment dysgenesis in the eyes of mice deficient for the high-mobility-group transcription factor Sox11. Experimental Eye Research 86 : 895–907.

14. MorrisAC, Forbes-OsborneMA, PillaiLS, FadoolJM (2011) Microarray Analysis of XOPS-mCFP Zebrafish Retina Identifies Genes Associated with Rod Photoreceptor Degeneration and Regeneration. Investigative Ophthalmology & Visual Science 52 : 2255–2266.

15. HeathcoteJG, SholdiceJ, WaltonJC, WillisNR, SergovichFR (1991) Anterior segment mesenchymal dysgenesis associated with partial duplication of the short arm of chromosome 2. Canadian journal of ophthalmology Journal canadien d'ophtalmologie 26 : 35–43.

16. Aviram-GoldringA, FritzB, BartschC, SteuberE, DanielyM, et al. (2000) Molecular cytogenetic studies in three patients with partial trisomy 2p, including CGH from paraffin-embedded tissue. American Journal of Medical Genetics 91 : 74–82.

17. TiradoCA, HendersonS, UddinN, StewartE, IyerS, et al. (2009) Cytogenetic and molecular characterization of a partial trisomy 2p arising from inverted duplication of 2p with terminal deletion of 2pter. American Journal of Medical Genetics Part A 149A: 2507–2512.

18. Lo-CastroA, GianaG, FicheraM, CastigliaL, GrilloL, et al. (2009) Deletion 2p25.2: A cryptic chromosome abnormality in a patient with autism and mental retardation detected using aCGH. European Journal of Medical Genetics 52 : 67–70.

19. RiminiR, BeltrameM, ArgentonF, SzymczakD, CotelliF, et al. (1999) Expression patterns of zebrafish sox11A, sox11B and sox21. Mechanisms of Development 89 : 167–171.

20. De MartinoS, YanY-L, JowettT, PostlethwaitJH, VargaZM, et al. (2000) Expression of sox11 gene duplicates in zebrafish suggests the reciprocal loss of ancestral gene expression patterns in development. Developmental Dynamics 217 : 279–292.

21. NavratilovaP, FredmanD, LenhardB, BeckerTS (2010) Regulatory divergence of the duplicated chromosomal loci sox11a/b by subpartitioning and sequence evolution of enhancers in zebrafish. Molecular genetics and genomics : MGG 283 : 171–184.

22. HuM, EasterSSJr (1999) Retinal Neurogenesis: The Formation of the Initial Central Patch of Postmitotic Cells. Developmental Biology 207 : 309–321.

23. NeumannCJ, Nuesslein-VolhardC (2000) Patterning of the Zebrafish Retina by a Wave of Sonic Hedgehog Activity. Science 289 : 2137–2139.

24. VinothkumarS, RastegarS, TakamiyaM, ErtzerR, SträhleU (2008) Sequential and cooperative action of Fgfs and Shh in the zebrafish retina. Developmental Biology 314 : 200–214.

25. LeeJ, WillerJR, WillerGB, SmithK, GreggRG, et al. (2008) Zebrafish blowout provides genetic evidence for Patched1-mediated negative regulation of Hedgehog signaling within the proximal optic vesicle of the vertebrate eye. Developmental Biology 319 : 10–22.

26. LeeJ, CoxBD, DalyCMS, LeeC, NuckelsRJ, et al. (2012) An ENU Mutagenesis Screen in Zebrafish for Visual System Mutants Identifies a Novel Splice-Acceptor Site Mutation in patched2 that Results in Colobomas. Investigative Ophthalmology & Visual Science 53 : 8214–8221.

27. KimT-H, GoodmanJ, AndersonKV, NiswanderL (2007) Phactr4 Regulates Neural Tube and Optic Fissure Closure by Controlling PP1-, Rb-, and E2F1-Regulated Cell-Cycle Progression. Developmental Cell 13 : 87–102.

28. FadoolJM (2003) Development of a rod photoreceptor mosaic revealed in transgenic zebrafish. Developmental Biology 258 : 277–290.

29. ShenY-c, RaymondPA (2004) Zebrafish cone-rod (crx) homeobox gene promotes retinogenesis. Developmental Biology 269 : 237–251.

30. ChenJ, RattnerA, NathansJ (2005) The Rod Photoreceptor-Specific Nuclear Receptor Nr2e3 Represses Transcription of Multiple Cone-Specific Genes. The Journal of Neuroscience 25 : 118–129.

31. OchocinskaMJ, HitchcockPF (2009) NeuroD regulates proliferation of photoreceptor progenitors in the retina of the zebrafish. Mechanisms of Development 126 : 128–141.

32. BruhnS, CepkoC (1996) Development of the pattern of photoreceptors in the chick retina. The Journal of Neuroscience 16 : 1430–1439.

33. Stenkamp DL (2007) Neurogenesis in the Fish Retina. In: Kwang WJ, editor. International Review of Cytology: Academic Press. pp. 173–224.

34. ShenM-C, OzacarAT, OsgoodM, BoerasC, PinkJ, et al. (2013) Heat-shock–mediated conditional regulation of hedgehog/gli signaling in zebrafish. Developmental Dynamics 242 : 539–549.

35. NaseviciusA, EkkerSC (2000) Effective targeted gene ‘knockdown’ in zebrafish. Nature genetics 26 : 216–220.

36. BergslandM, RamskoldD, ZaouterC, KlumS, SandbergR, et al. (2011) Sequentially acting Sox transcription factors in neural lineage development. Genes & development 25 : 2453–2464.

37. WiebeMS, NowlingTK, RizzinoA (2003) Identification of Novel Domains within Sox-2 and Sox-11 Involved in Autoinhibition of DNA Binding and Partnership Specificity. Journal of Biological Chemistry 278 : 17901–17911.

38. ChewL-J, GalloV (2009) The Yin and Yang of Sox proteins: Activation and repression in development and disease. Journal of Neuroscience Research 87 : 3277–3287.

39. MukhopadhyayA, KrishnaswamiSR, Cowing-ZitronC, HungN-J, Reilly-RhotenH, et al. (2013) Negative regulation of Shh levels by Kras and Fgfr2 during hair follicle development. Developmental Biology 373 : 373–382.

40. ManningL, OhyamaK, SaegerB, HatanoO, WilsonSA, et al. (2006) Regional Morphogenesis in the Hypothalamus: A BMP-Tbx2 Pathway Coordinates Fate and Proliferation through Shh Downregulation. Developmental Cell 11 : 873–885.

41. ShawiM, SerlucaFC (2008) Identification of a BMP7 homolog in zebrafish expressed in developing organ systems. Gene Expression Patterns 8 : 369–375.

42. BastidaMF, ShethR, RosMA (2009) A BMP-Shh negative-feedback loop restricts Shh expression during limb development. Development 136 : 3779–3789.

43. FarinHF, LüdtkeTHW, SchmidtMK, PlaczkoS, Schuster-GosslerK, et al. (2013) Tbx2 Terminates Shh/Fgf Signaling in the Developing Mouse Limb Bud by Direct Repression of Gremlin1. PLoS Genet 9: e1003467.

44. TakabatakeY, TakabatakeT, SasagawaS, TakeshimaK (2002) Conserved expression control and shared activity between cognate T-box genes Tbx2 and Tbx3 in connection with Sonic hedgehog signaling during Xenopus eye development. Development, Growth & Differentiation 44 : 257–271.

45. MorcilloJ, Martínez-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.

46. DyP, Penzo-MéndezA, WangH, PedrazaCE, MacklinWB, et al. (2008) The three SoxC proteins—Sox4, Sox11 and Sox12—exhibit overlapping expression patterns and molecular properties. Nucleic Acids Research 36 : 3101–3117.

47. YeM, Berry-WynneKM, Asai-CoakwellM, SundaresanP, FootzT, et al. (2010) Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies. Human Molecular Genetics 19 : 287–298.

48. Asai-CoakwellM, FrenchCR, BerryKM, YeM, KossR, et al. (2007) GDF6, a Novel Locus for a Spectrum of Ocular Developmental Anomalies. The American Journal of Human Genetics 80 : 306–315.

49. Asai-CoakwellM, FrenchCR, YeM, GarchaK, BigotK, et al. (2009) Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes. Human Molecular Genetics 18 : 1110–1121.

50. KanA, IkedaT, FukaiA, NakagawaT, NakamuraK, et al. (2013) SOX11 contributes to the regulation of GDF5 in joint maintenance. BMC developmental biology 13 : 4.

51. UsuiA, MochizukiY, IidaA, MiyauchiE, SatohS, et al. (2013) The early retinal progenitor-expressed gene Sox11 regulates the timing of the differentiation of retinal cells. Development 140 : 740–750.

52. MacdonaldR, BarthKA, XuQ, HolderN, MikkolaI, et al. (1995) Midline signalling is required for Pax gene regulation and patterning of the eyes. Development 121 : 3267–3278.

53. PerronM, BoyS, AmatoMA, ViczianA, KoebernickK, et al. (2003) A novel function for Hedgehog signalling in retinal pigment epithelium differentiation. Development 130 : 1565–1577.

54. ShahamO, SmithAN, RobinsonML, TaketoMM, LangRA, et al. (2009) Pax6 is essential for lens fiber cell differentiation. Development 136 : 2567–2578.

55. MartíE, BovolentaP (2002) Sonic hedgehog in CNS development: one signal, multiple outputs. Trends in Neurosciences 25 : 89–96.

56. StenkampDL, FreyRA, PrabhudesaiSN, RaymondPA (2000) Function for Hedgehog Genes in Zebrafish Retinal Development. Developmental Biology 220 : 238–252.

57. YuC, MazerolleCJ, ThurigS, WangY, PacalM, et al. (2006) Direct and indirect effects of hedgehog pathway activation in the mammalian retina. Molecular and cellular neurosciences 32 : 274–282.

58. WangY, DakuboGD, ThurigS, MazerolleCJ, WallaceVA (2005) Retinal ganglion cell-derived sonic hedgehog locally controls proliferation and the timing of RGC development in the embryonic mouse retina. Development 132 : 5103–5113.

59. SirkoS, BehrendtG, Johansson PiaA, TripathiP, CostaMR, et al. (2013) Reactive Glia in the Injured Brain Acquire Stem Cell Properties in Response to Sonic Hedgehog. Cell Stem Cell 12 : 426–439.

60. SchedlA, RossA, LeeM, EngelkampD, RashbassP, et al. (1996) Influence of PAX6 Gene Dosage on Development: Overexpression Causes Severe Eye Abnormalities. Cell 86 : 71–82.

61. KayJN, LinkBA, BaierH (2005) Staggered cell-intrinsic timing of ath5 expression underlies the wave of ganglion cell neurogenesis in the zebrafish retina. Development 132 : 2573–2585.

62. BrzezinskiJAt, PrasovL, GlaserT (2012) Math5 defines the ganglion cell competence state in a subpopulation of retinal progenitor cells exiting the cell cycle. Developmental Biology 365 : 395–413.

63. KayJN, Finger-BaierKC, RoeserT, StaubW, BaierH (2001) Retinal ganglion cell genesis requires lakritz, a zebrafish atonal homolog. Neuron 30 : 725–736.

64. StenkampDL, FreyRA (2003) Extraretinal and retinal hedgehog signaling sequentially regulate retinal differentiation in zebrafish. Developmental Biology 258 : 349–363.

65. LevineEM, RoelinkH, TurnerJ, RehTA (1997) Sonic Hedgehog Promotes Rod Photoreceptor Differentiation in Mammalian Retinal Cells In Vitro. The Journal of Neuroscience 17 : 6277–6288.

66. WangYP, DakuboG, HowleyP, CampsallKD, MazarolleCJ, et al. (2002) Development of normal retinal organization depends on Sonic hedgehog signaling from ganglion cells. Nature neuroscience 5 : 831–832.

67. BlackGCM, MazerolleCJ, WangY, CampsallKD, PetrinD, et al. (2003) Abnormalities of the vitreoretinal interface caused by dysregulated Hedgehog signaling during retinal development. Human Molecular Genetics 12 : 3269–3276.

68. LiemKFJr, TremmlG, RoelinkH, JessellTM (1995) Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell 82 : 969–979.

69. DavisEE, KatsanisN (2012) The ciliopathies: a transitional model into systems biology of human genetic disease. Current Opinion in Genetics & Development 22 : 290–303.

70. BhattaramP, Penzo-MendezA, SockE, ColmenaresC, KanekoKJ, et al. (2010) Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors. Nature communications 1 : 9.

71. ReisL, TylerR, SchilterK, Abdul-RahmanO, InnisJ, et al. (2011) BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome. Human Genetics 130 : 495–504.

72. BakraniaP, EfthymiouM, KleinJC, SaltA, BunyanDJ, et al. (2008) Mutations in BMP4 Cause Eye, Brain, and Digit Developmental Anomalies: Overlap between the BMP4 and Hedgehog Signaling Pathways. The American Journal of Human Genetics 82 : 304–319.

73. MihelecM, AbrahamP, GibsonK, KrowkaR, SusmanR, et al. (2009) Novel SOX2 partner-factor domain mutation in a four-generation family. European journal of human genetics : EJHG 17 : 1417–1422.

74. BernardosRL, RaymondPA (2006) GFAP transgenic zebrafish. Gene Expression Patterns 6 : 1007–1013.

75. KennedyBN, AlvarezY, BrockerhoffSE, StearnsGW, Sapetto-RebowB, et al. (2007) Identification of a Zebrafish Cone Photoreceptor–Specific Promoter and Genetic Rescue of Achromatopsia in the nof Mutant. Investigative Ophthalmology & Visual Science 48 : 522–529.

76. Westerfield M, 1995 (Westerfield, M.,1995) The zebrafish book. A guide for the laboratory use of zebrafish (Danio rerio). 4th ed, Univ of Oregon Press, Eugene.

77. KimmelCB, BallardWW, KimmelSR, UllmannB, SchillingTF (1995) Stages of embryonic development of the zebrafish. Developmental Dynamics 203 : 253–310.

78. Forbes-OsborneMA, WilsonSG, MorrisAC (2013) Insulinoma-associated 1a (Insm1a) is required for photoreceptor differentiation in the zebrafish retina. Developmental Biology 380 : 157–171.

79. McCurleyAT, CallardGV (2008) Characterization of housekeeping genes in zebrafish: male-female differences and effects of tissue type, developmental stage and chemical treatment. BMC molecular biology 9 : 102.

80. KanA, IkedaT, FukaiA, NakagawaT, NakamuraK, et al. (2013) SOX11 contributes to the regulation of GDF5 in joint maintenance. BMC Dev Biol 13 : 4 10.1186/1471-1213X-1113-1184