A Regulatory Loop Involving PAX6, MITF, and WNT Signaling Controls Retinal Pigment Epithelium Development
The separation of the optic neuroepithelium into future retina and retinal pigment epithelium (RPE) is a critical event in early eye development in vertebrates. Here we show in mice that the transcription factor PAX6, well-known for its retina-promoting activity, also plays a crucial role in early pigment epithelium development. This role is seen, however, only in a background genetically sensitized by mutations in the pigment cell transcription factor MITF. In fact, a reduction in Pax6 gene dose exacerbates the RPE-to-retina transdifferentiation seen in embryos homozygous for an Mitf null allele, and it induces such a transdifferentiation in embryos that are either heterozygous for the Mitf null allele or homozygous for an RPE–specific hypomorphic Mitf allele generated by targeted mutation. Conversely, an increase in Pax6 gene dose interferes with transdifferentiation even in homozygous Mitf null embryos. Gene expression analyses show that, together with MITF or its paralog TFEC, PAX6 suppresses the expression of Fgf15 and Dkk3. Explant culture experiments indicate that a combination of FGF and DKK3 promote retina formation by inhibiting canonical WNT signaling and stimulating the expression of retinogenic genes, including Six6 and Vsx2. Our results demonstrate that in conjunction with Mitf/Tfec Pax6 acts as an anti-retinogenic factor, whereas in conjunction with retinogenic genes it acts as a pro-retinogenic factor. The results suggest that careful manipulation of the Pax6 regulatory circuit may facilitate the generation of retinal and pigment epithelium cells from embryonic or induced pluripotent stem cells.
Vyšlo v časopise:
A Regulatory Loop Involving PAX6, MITF, and WNT Signaling Controls Retinal Pigment Epithelium Development. PLoS Genet 8(7): e32767. doi:10.1371/journal.pgen.1002757
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002757
Souhrn
The separation of the optic neuroepithelium into future retina and retinal pigment epithelium (RPE) is a critical event in early eye development in vertebrates. Here we show in mice that the transcription factor PAX6, well-known for its retina-promoting activity, also plays a crucial role in early pigment epithelium development. This role is seen, however, only in a background genetically sensitized by mutations in the pigment cell transcription factor MITF. In fact, a reduction in Pax6 gene dose exacerbates the RPE-to-retina transdifferentiation seen in embryos homozygous for an Mitf null allele, and it induces such a transdifferentiation in embryos that are either heterozygous for the Mitf null allele or homozygous for an RPE–specific hypomorphic Mitf allele generated by targeted mutation. Conversely, an increase in Pax6 gene dose interferes with transdifferentiation even in homozygous Mitf null embryos. Gene expression analyses show that, together with MITF or its paralog TFEC, PAX6 suppresses the expression of Fgf15 and Dkk3. Explant culture experiments indicate that a combination of FGF and DKK3 promote retina formation by inhibiting canonical WNT signaling and stimulating the expression of retinogenic genes, including Six6 and Vsx2. Our results demonstrate that in conjunction with Mitf/Tfec Pax6 acts as an anti-retinogenic factor, whereas in conjunction with retinogenic genes it acts as a pro-retinogenic factor. The results suggest that careful manipulation of the Pax6 regulatory circuit may facilitate the generation of retinal and pigment epithelium cells from embryonic or induced pluripotent stem cells.
Zdroje
1. BhartiKNguyenMTSkuntzSBertuzziSArnheiterH 2006 The other pigment cell: specification and development of the pigmented epithelium of the vertebrate eye. Pigment Cell Research 19 380 394
2. KarlMORehTA 2010 Regenerative medicine for retinal diseases: activating endogenous repair mechanisms. Trends Mol Med 16 193 202
3. MillerSSMaminishkisALiRAdijantoJ 2010 Retinal Pigment Epithelium: Cytokine Modulation of Epithelial Physiology. DarttDA Encyclopedia of the Eye: Oxford University Academic Press 89 100 editor pp
4. HemesathTJSteingrimssonEMcGillGHansenMJVaughtJ 1994 microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Genes Dev 8 2770 2780
5. HodgkinsonCAMooreKJNakayamaASteingrimssonECopelandNG 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
6. HorsfordDJNguyenMTSellarGCKotharyRArnheiterH 2005 Chx10 repression of Mitf is required for the maintenance of mammalian neuroretinal identity. Development 132 177 187
7. NguyenMArnheiterH 2000 Signaling and transcriptional regulation in early mammalian eye development: a link between FGF and MITF. Development 127 3581 3591
8. FujimuraNTaketoMMMoriMKorinekVKozmikZ 2009 Spatial and temporal regulation of Wnt/beta-catenin signaling is essential for development of the retinal pigment epithelium. Dev Biol 334 31 45
9. GrocottTJohnsonSBaileyAPStreitA 2011 Neural crest cells organize the eye via TGF-beta and canonical Wnt signalling. Nat Commun 2 265
10. MüllerFRohrerHVogel-HopkerA 2007 Bone morphogenetic proteins specify the retinal pigment epithelium in the chick embryo. Development 134 3483 3493
11. WestenskowPPiccoloSFuhrmannS 2009 Beta-catenin controls differentiation of the retinal pigment epithelium in the mouse optic cup by regulating Mitf and Otx2 expression. Development 136 2505 2510
12. FuhrmannSLevineEMRehTA 2000 Extraocular mesenchyme patterns the optic vesicle during early eye development in the embryonic chick. Development 127 4599 4609
13. BumstedKMBarnstableCJ 2000 Dorsal retinal pigment epithelium differentiates as neural retina in the microphthalmia (mi/mi) mouse. Invest Ophthalmol Vis Sci 41 903 908
14. BhartiKLiuWCsermelyTBertuzziSArnheiterH 2008 Alternative promoter use in eye development: the complex role and regulation of the transcription factor MITF. Development 135 1169 1178
15. GrindleyJCDavidsonDRHillRE 1995 The role of Pax-6 in eye and nasal development. Development 121 1433 1442
16. Martinez-MoralesJRRodrigoIBovolentaP 2004 Eye development: a view from the retina pigmented epithelium. Bioessays 26 766 777
17. QuinnJCWestJDHillRE 1996 Multiple functions for Pax6 in mouse eye and nasal development. Genes Dev 10 435 446
18. HillREFavorJHoganBLTonCCSaundersGF 1991 Mouse small eye results from mutations in a paired-like homeobox-containing gene. Nature 354 522 525
19. MarquardtTAshery-PadanRAndrejewskiNScardigliRGuillemotF 2001 Pax6 is required for the multipotent state of retinal progenitor cells. Cell 105 43 55
20. SchedlARossALeeMEngelkampDRashbassP 1996 Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities. Cell 86 71 82
21. ManuelMPrattTLiuMJefferyGPriceDJ 2008 Overexpression of Pax6 results in microphthalmia, retinal dysplasia and defective retinal ganglion cell axon guidance. BMC Dev Biol 8 59
22. CollinsonJMQuinnJCHillREWestJD 2003 The roles of Pax6 in the cornea, retina, and olfactory epithelium of the developing mouse embryo. Dev Biol 255 303 312
23. PlanqueNLeconteLCoquelleFMMartinPSauleS 2001 Specific Pax-6/microphthalmia transcription factor interactions involve their DNA-binding domains and inhibit transcriptional properties of both proteins. J Biol Chem 276 29330 29337
24. BäumerNMarquardtTStoykovaASpielerDTreichelD 2003 Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6. Development 130 2903 2915
25. KosoHIidaATabataYBabaYSatohS 2008 CD138/syndecan-1 and SSEA-1 mark distinct populations of developing ciliary epithelium that are regulated differentially by Wnt signal. Stem Cells 26 3162 3171
26. MuiSHKimJWLemkeGBertuzziS 2005 Vax genes ventralize the embryonic eye. Genes Dev 19 1249 1259
27. TangKXieXParkJIJamrichMTsaiS 2010 COUP-TFs regulate eye development by controlling factors essential for optic vesicle morphogenesis. Development 137 725 734
28. RowanSChenCMYoungTLFisherDECepkoCL 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
29. MurisierFGuichardSBeermannF 2007 Distinct distal regulatory elements control tyrosinase expression in melanocytes and the retinal pigment epithelium. Dev Biol 303 838 847
30. KuiperRPSchepensMThijssenJSchoenmakersEFvan KesselAG 2004 Regulation of the MiTF/TFE bHLH-LZ transcription factors through restricted spatial expression and alternative splicing of functional domains. Nucleic Acids Res 32 2315 2322
31. GuillemotFCepkoCL 1992 Retinal fate and ganglion cell differentiation are potentiated by acidic FGF in an in vitro assay of early retinal development. Development 114 743 754
32. ZhaoSThornquistSCBarnstableCJ 1995 In vitro transdifferentiation of embryonic rat retinal pigment epithelium to neural retina. Brain Res 677 300 310
33. NiehrsC 2006 Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 25 7469 7481
34. YueWSunQDacicSLandreneauRJSiegfriedJM 2008 Downregulation of Dkk3 activates beta-catenin/TCF-4 signaling in lung cancer. Carcinogenesis 29 84 92
35. NakamuraREHunterDDYiHBrunkenWJHackamAS 2007 Identification of two novel activities of the Wnt signaling regulator Dickkopf 3 and characterization of its expression in the mouse retina. BMC Cell Biol 8 52
36. GuillemotFZimmerC 2011 From cradle to grave: The multiple roles of fibroblast growth factors in neural development. Neuron 71 574 588
37. MohamedOAClarkeHJDufortD 2004 Beta-catenin signaling marks the prospective site of primitive streak formation in the mouse embryo. Dev Dyn 231 416 424
38. ZuberMEGestriGViczianASBarsacchiGHarrisWA 2003 Specification of the vertebrate eye by a network of eye field transcription factors. Development 130 5155 5167
39. EirakuMTakataNIshibashiHKawadaMSakakuraE 2011 Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472 51 56
40. MatsushimaDHeavnerWPevnyLH 2011 Combinatorial regulation of optic cup progenitor cell fate by SOX2 and PAX6. Development 138 443 454
41. HyerJMimaTMikawaT 1998 FGF1 patterns the optic vesicle by directing the placement of the neural retina domain. Development 125 869 877
42. BhartiKMillerSSArnheiterH 2011 The new paradigm: retinal pigment epithelium cells generated from embryonic or induced pluripotent stem cells. Pigment Cell Melanoma Res 24 21 34
43. CamposMAmaralJBecerraSPFarissRN 2006 A novel imaging technique for experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 47 5163 5170
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 7
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Guidelines for Genome-Wide Association Studies
- The Role of Rice HEI10 in the Formation of Meiotic Crossovers
- Identification of Chromatin-Associated Regulators of MSL Complex Targeting in Dosage Compensation
- GWAS Identifies Novel Susceptibility Loci on 6p21.32 and 21q21.3 for Hepatocellular Carcinoma in Chronic Hepatitis B Virus Carriers