This abundance of putative TFBSs highlights the remaining challenge to determine which TFBSs play a role in activating or repressing IRBP transcription. This problem is solvable, as illustrated by the important work on the very limited number of these trans factors that we discussed above.

The Chx10 site between 48,012,428 and 48,012,441 in the upstream conserved region might play a role in the repression of IRBP transcription in nonphotoreceptor retinal cells. It is worth consideration of the binding properties of Chx10 in the proximal part and the upstream conserved region of the IRBP promoter [111]. It was found that in vitro in EMSAs Chx10 can bind to the Ret1/PCE I site in the proximal promoter and to the Chx10 site in the upstream conserved element. However, by in vivo CHiP assay, they found that Chx10 does not bind well to the proximal Ret1/PCE I element immediately adjacent to the CRX-binding site on the IRBP promoter. Importantly, it was found that Chx10 is strongly associated with the IRBP upstream conserved element. These findings were the same whether using mice at P0, P6, or P14. These findings may be affected by the use of whole neural retinas, as opposed to cell-type-specific chromatin (cf., from purified rod photoreceptors or highly enriched populations containing bipolar cells only).

SUMMARY AND CONJECTURE

Transcription factors have been identified that activate or repress the IRBP promoter activity in vitro, but their role in the control of IRBP gene expression in vivo is uncertain. Likely candidates for transcription factors that activate IRBP gene transcription and control its tissue-specific expression in adult photoreceptors are Crx, Nrl, and Otx2. These photoreceptor transcription factors do not work independently in the regulation of IRBP gene expression because the proteins pairs of Crx/Nrl and Otx2/Nrl work synergistically in transactivation assays [88, 95]. Interactions between these transcription factors may be different in rods versus cones.

Crx transactivates the IRBP promoter in vitro. When mice carrying a transgene that consists of the IRBP promoter with a mutation in the CRX element upstream of a reporter gene, reporter gene expression is not found in photoreceptor cells of any of the transgenic mouse lines, indicating that the CRX element is necessary for IRBP expression in vivo [86]. Expression patterns of IRBP and the Crx element during retina development in the mouse are very similar to each other. The Crx message is first detected at E10.5 by rtPCR in mouse embryonic eyes [36], while IRBP is detected by RPA at E11.5 [35]. In the mouse, E12.5 is the time of cone cell genesis [33]. CRx protein is found in the neural developing retina at E12.5, and it is highly expressed in the adult [73, 74]. Surprisingly, however, IRBP expression levels appear unchanged in Crx null mice compared to wildtype mice [97], suggesting that Crx expression is not required for IRBP expression. Suppression of Crx by antisense treatment results in loss of promoter activity for p70, suggesting that while Crx is not absolutely requisite (Otx2 may be substituting), it may be the endogenous factor under normal (e.g., not knockout) situations [100].

Otx2 has an implied function in the activation of the IRBP gene; however, Otx2 expression in the adult is weak, suggesting that Otx2 is not the primary activator of IRBP gene expression in the adult. But, Crx expression is robust in adult photoreceptor cells. Crx and Otx2 are both members of the Otx gene family, which contains the

paired class of homeodomain within their proteins. Homeodomain-containing proteins bind to DNA as a monomer, different homeodomain proteins can bind to the same DNA sequences, and other mechanisms are needed to achieve functional specificity for specific homeodomain transcription factors [117]. Perhaps there is a redundancy of function between Crx and Otx2. In the Crx null mice in which IRBP expression is basically normal, adequate amounts of Otx2 protein may be present and sufficient to maintain IRBP expression levels in the adult.

Another transcription factor that may be required for IRBP gene expression is Rx/ rax, which is known to transactivate the IRBP promoter in vitro. During development, Rx is located at the correct time and place to activate IRBP gene expression in early retinal development. However, later in development, Rx expression in the retina becomes very low at E13.5 [118], whereas there is robust IRBP expression at this age. This indicates that the Rx/rax gene expression does not have a role in IRBP gene expression in the adult. Clearly, there are transcription factors that are required for the correct spatial and temporal expression of the IRBP gene that are yet to be identified.

The retina is an excellent model for the study of brain development because it is part of the central nervous system, is easily accessible, and has a layered organization. Unlike many transcription factors found in the brain, retina-specific proteins are not required for viability and fertility, so null mutations do not have an adverse affect on the overall health of the animal. The mechanisms of cell fate determination and the gene families expressed by the progenitor cells are shared by the retina, cortex, and cerebellum.

ACKNOWLEDGMENTS

This work was supported by NIH EY11726 (D.E.B.), USU-CO70VY (D.E.B.), EY12514 (J.B.), R01EY014026 (J.B.), R01EY016470, R03EY013986, R24EY017045, and P30EY006360; the Foundation Fighting Blindness; Fight for Sight; Research to Prevent Blindness Inc.; and Knights Templar of Georgia.

REFERENCES

1.Crouch RK, Hazard ES, Lind T, Wiggert B, Chader G, Corson DW. Interphotoreceptor retin- oid-binding protein and alpha-tocopherol preserve the isomeric and oxidation state of retinol. Photochem Photobiol 1992;56(2):251–255.

2.Pfeffer B, Wiggert B, Lee L, Zonnenberg B, Newsome D, Chader G. The presence of a soluble interphotoreceptor retinol-binding protein (IRBP) in the retinal interphotoreceptor space. J Cell Physiol 1983;117(3):333–341.

3.Wiggert B, Lee L, Rodrigues M, Hess H, Redmond TM, Chader GJ. Immunochemical distribution of interphotoreceptor retinoid-binding protein in selected species. Invest Ophthalmol Vis Sci 1986;27(7):1041–1049.

4.Rodrigues MM, Hackett J, Gaskins R, Wiggert B, Lee L, Redmond M, et al. Interphotoreceptor retinoid-binding protein in retinal rod cells and pineal gland. Invest Ophthalmol Vis Sci 1986;27(5):844–850.

5.Chen Y, Saari JC, Noy N. Interactions of all-trans-retinol and long-chain fatty acids with interphotoreceptor retinoid-binding protein. Biochemistry 1993;32(42):11311–11318.

6.Chen Y, Houghton LA, Brenna JT, Noy N. Docosahexaenoic acid modulates the interactions of the interphotoreceptor retinoid-binding protein with 11-cis-retinal. J Biol Chem 1996;271(34):20507–20515.

7.Fong SL, Liou GI, Landers RA, Alvarez RA, Bridges CD. Purification and characterization of a retinol-binding glycoprotein synthesized and secreted by bovine neural retina. J Biol Chem 1984;259(10):6534–6542.

8.Lai YL, Wiggert B, Liu YP, Chader GJ. Interphotoreceptor retinol-binding proteins: possible transport vehicles between compartments of the retina. Nature 1982;298(5877):848–849.

9.Saari JC, Teller DC, Crabb JW, Bredberg L. Properties of an interphotoreceptor retinoidbinding protein from bovine retina. J Biol Chem 1985;260(1):195–201.

10.Nickerson JM, Li GR, Lin ZY, Takizawa N, Si JS, Gross EA. Structure-function relationships in the four repeats of human interphotoreceptor retinoid-binding protein (IRBP). Mol Vis 1998;4:33.

11.Lin ZY, Li GR, Takizawa N, Si JS, Gross EA, Richardson K, et al. Structure-function relationships in interphotoreceptor retinoid-binding protein (IRBP). Mol Vis 1997;3:17.

12.Lin ZY, Si JS, Nickerson JM. Biochemical and biophysical properties of recombinant human interphotoreceptor retinoid binding protein. Invest Ophthalmol Vis Sci 1994;35(10):3599–3612.

13.Baer CA, Retief JD, Van Niel E, Braiman MS, Gonzalez-Fernandez F. Soluble expression in E. coli of a functional interphotoreceptor retinoid-binding protein module fused to thioredoxin: correlation of vitamin A binding regions with conserved domains of C-terminal processing proteases. Exp Eye Res 1998;66(2):249–262.

14.Baer CA, Kittredge KL, Klinger AL, Briercheck DM, Braiman MS, Gonzalez-Fernandez F. Expression and characterization of the fourth repeat of Xenopus interphotoreceptor retinoidbinding protein in E. coli. Curr Eye Res 1994;13(6):391–400.

15.Gonzalez-Fernandez F, Kittredge KL, Rayborn ME, Hollyfield JG, Landers RA, Saha M, et al. Interphotoreceptor retinoid-binding protein (IRBP), a major 124 kDa glycoprotein in the interphotoreceptor matrix of Xenopus laevis. Characterization, molecular cloning and biosynthesis. J Cell Sci 1993;105(Pt 1):7–21.

16.Hessler RB, Baer CA, Bukelman A, Kittredge KL, Gonzalez-Fernandez F. Interphotoreceptor retinoid-binding protein (IRBP): expression in the adult and developing Xenopus retina. J Comp Neurol 1996;367(3):329–341.

17.Liou GI, Fei Y, Peachey NS, Matragoon S, Wei S, Blaner WS, et al. Early onset photoreceptor abnormalities induced by targeted disruption of the interphotoreceptor retinoid-binding protein gene. J Neurosci 1998;18(12):4511–4520.

18.Ripps H, Peachey NS, Xu X, Nozell SE, Smith SB, Liou GI. The rhodopsin cycle is preserved in IRBP “knockout” mice despite abnormalities in retinal structure and function. Vis Neurosci 2000;17(1):97–105.

19.Donmoyer CM, Ciavatta VT, Liou GI, Nickerson JM. Microarray analysis of the neonatal Irbp knockout mouse. Invest Ophthalmol Vis Sci 2006;47:E-Abstract 4895.

20.Chader GJ. Retinal degenerations of hereditary, viral and autoimmune origins: studies on opsin and IRBP. Prog Retin Eye Res 1994;13(1):65–99.

21.Redmond TM, Sanui H, Nickerson JM, Borst DE, Wiggert B, Kuwabara T, et al. Cyanogen bromide fragments of bovine interphotoreceptor retinoid-binding protein induce experimental autoimmune uveoretinitis in Lewis rats. Curr Eye Res 1988;7(4):375–385.

22.Redmond TM, Si JS, Barrett DJ, Borst DE, Rainier S, Kotake S, et al. Synthesis of an immunopathogenic fusion protein derived from a bovine interphotoreceptor retinoid-binding protein cDNA clone. Gene 1989;80(1):109–118.

23.Kotake S, Wiggert B, Redmond TM, Borst DE, Nickerson JM, Margalit H, et al. Repeated determinants within the retinal interphotoreceptor retinoid-binding protein (IRBP): immunological properties of the repeats of an immunodominant determinant. Cell Immunol 1990;126(2):331–342.

24.Xu H, Wawrousek EF, Redmond TM, Nickerson JM, Wiggert B, Chan CC, et al. Transgenic expression of an immunologically privileged retinal antigen extraocularly enhances self

tolerance and abrogates susceptibility to autoimmune uveitis. Eur J Immunol 2000;30(1): 272–278.

25.Avichezer D, Liou GI, Chan CC, Lewis GM, Wiggert B, Donoso LA, et al. Interphotoreceptor retinoid-binding protein (IRBP)-deficient C57BL/6 mice have enhanced immunological and immunopathogenic responses to IRBP and an altered recognition of IRBP epitopes. J Autoimmun 2003;21(3):185–194.

26.Grajewski RS, Silver PB, Agarwal RK, Su SB, Chan CC, Liou GI, et al. Endogenous IRBP can be dispensable for generation of natural CD4+CD25+ regulatory T cells that protect from IRBP-induced retinal autoimmunity. J Exp Med 2006;203(4):851–856.

27.Turner DL, Cepko CL. A common progenitor for neurons and glia persists in rat retina late in development. Nature 1987;328(6126):131–136.

28.Holt CE, Bertsch TW, Ellis HM, Harris WA. Cellular determination in the Xenopus retina is independent of lineage and birth date. Neuron 1988;1(1):15–26.

29.Wetts R, Fraser SE. Multipotent precursors can give rise to all major cell types of the frog retina. Science 1988;239(4844):1142–1145.

30.Turner DL, Snyder EY, Cepko CL. Lineage-independent determination of cell type in the embryonic mouse retina. Neuron 1990;4(6):833–845.

31.Young RW. Cell differentiation in the retina of the mouse. Anat Rec 1985;212:199–205.

32.Rapaport DH, Wong LL, Wood ED, Yasumura D, LaVail MM. Timing and topography of cell genesis in the rat retina. J Comp Neurol 2004;474(2):304–324.

33.Carter-Dawson LD, LaVail MM. Rods and cones in the mouse retina. II. Autoradiographic analysis of cell generation using tritiated thymidine. J Comp Neurol 1979;188(2):263–272.

34.Carter-Dawson L, Alvarez RA, Fong SL, Liou GI, Sperling HG, Bridges CD. Rhodopsin, 11-cis vitamin A, and interstitial retinol-binding protein (IRBP) during retinal development in normal and rd mutant mice. Dev Biol 1986;116(2):431–438.

35.Liou GI, Wang M, Matragoon S. Timing of interphotoreceptor retinoid-binding protein (IRBP) gene expression and hypomethylation in developing mouse retina. Dev Biol 1994;161(2):345–356.

36.Bibb LC, Holt JK, Tarttelin EE, Hodges MD, Gregory-Evans K, Rutherford A, et al. Temporal and spatial expression patterns of the CRX transcription factor and its downstream targets. Critical differences during human and mouse eye development. Hum Mol Genet 2001;10(15):1571–1579.

37.Farr EA, Borst DE, Chader GJ, Bradley DJ. Developmental regulation of the mouse interphotoreceptor retinol binding protein gene in the fetal and post-natal eye. Invest Ophthalmol Vis Sci 1994;34:1727, Abstract 2199.

38.O’Brien KM, Schulte D, Hendrickson AE. Expression of photoreceptor-associated molecules during human fetal eye development. Mol Vis 2003;9:401–409.

39.Lee TC, Almeida D, Claros N, Abramson DH, Cobrinik D. Cell cycle-specific and cell type-specific expression of rb in the developing human retina. Invest Ophthalmol Vis Sci 2006;47(12):5590–5598.

40.Kutty G, Duncan T, Nickerson JM, Si JS, Van Veen T, Chader GJ, et al. Light deprivation profoundly affects gene expression of interphotoreceptor retinoid-binding protein in the mouse eye. Exp Eye Res 1994;58(1):65–75.

41.Katz ML, Gao CL, Stientjes HJ. Regulation of the interphotoreceptor retinoid-binding protein content of the retina by vitamin A. Exp Eye Res 1993;57(4):393–401.

42.Fong SL, Bridges CD. Internal quadruplication in the structure of human interstitial retinolbinding protein deduced from its cloned cDNA. J Biol Chem 1988;263(30):15330–15334.

43.Borst DE, Redmond TM, Elser JE, Gonda MA, Wiggert B, Chader GJ, et al. Interphotoreceptor retinoid-binding protein. Gene characterization, protein repeat structure, and its evolution. J Biol Chem 1989;264(2):1115–1123.

44.Barrett DJ, Redmond TM, Wiggert B, Oprian DD, Chader GJ, Nickerson JM. cDNA clones encoding bovine interphotoreceptor retinoid binding protein. Biochem Biophys Res Commun 1985;131(3):1086–1093.

45.Liou GI, Ma DP, Yang YW, Geng L, Zhu C, Baehr W. Human interstitial retinoid-binding protein. Gene structure and primary structure. J Biol Chem 1989;264(14):8200–8206.

46.Inouye LN, Albini A, Chader GJ, Redmond TM, Nickerson JM. mRNA for interphotoreceptor retinoid-binding protein (IRBP): distribution and size diversity in vertebrate species. Exp Eye Res 1989;49(2):171–180.

47.Liou GI, Geng L, Baehr W. Interphotoreceptor retinoid-binding protein: biochemistry and molecular biology. Prog Clin Biol Res 1991;362:115–137.

48.Stenkamp DL, Calderwood JL, Van Niel EE, Daniels LM, Gonzalez-Fernandez F. The interphotoreceptor retinoid-binding protein (IRBP) of the chicken (Gallus gallus domesticus). Mol Vis 2005;11:833–845.

49.Rajendran RR, Van Niel EE, Stenkamp DL, Cunningham LL, Raymond PA, GonzalezFernandez F. Zebrafish interphotoreceptor retinoid-binding protein: differential circadian expression among cone subtypes. J Exp Biol 1996;199(Pt 12):2775–2787.

50.Stenkamp DL, Cunningham LL, Raymond PA, Gonzalez-Fernandez F. Novel expression pattern of interphotoreceptor retinoid-binding protein (IRBP) in the adult and developing zebrafish retina and RPE. Mol Vis 1998;4:26.

51.Nickerson JM, Frey RA, Ciavatta VT, Stenkamp DL. Interphotoreceptor retinoid-binding protein gene structure in tetrapods and teleost fish. Mol Vis 2006;12:1565–1585.

52.Nickerson JM, Borst DE, Redmond TM, Si JS, Toffenetti J, Chader GJ. The molecular biology of IRBP: application to problems of uveitis, protein chemistry, and evolution. Prog Clin Biol Res 1991;362:139–161.

53.van Veen T, Katial A, Shinohara T, Barrett DJ, Wiggert B, Chader GJ, et al. Retinal photoreceptor neurons and pinealocytes accumulate mRNA for interphotoreceptor retinoid-binding protein (IRBP). FEBS Lett 1986;208(1):133–137.

54.Porrello K, Bhat SP, Bok D. Detection of interphotoreceptor retinoid binding protein (IRBP) mRNA in human and cone-dominant squirrel retinas by in situ hybridization. J Histochem Cytochem 1991;39(2):171–176.

55.Egwuagu CE, Charukamnoetkanok P, Gery I. Thymic expression of autoantigens correlates with resistance to autoimmune disease. J Immunol 1997;159(7):3109–3112.

56.Fong SL, Balakier H, Canton M, Bridges CD, Gallie B. Retinoid-binding proteins in retinoblastoma tumors. Cancer Res 1988;48(5):1124–1128.

57.Fong SL, Fong WB, Morris TA, Kedzie KM, Bridges CD. Characterization and comparative structural features of the gene for human interstitial retinol-binding protein. J Biol Chem 1990;265(7):3648–3653.

58.Shuler RK, Jr., Gross E, He WY, Liou GI, Nickerson JM. Sequence analysis of the mouse IRBP gene and cDNA. Curr Eye Res 2002;24(5):354–367.

59.Borst DE, Boatright JH, Si JS, Stodulkova E, Remaley N, Pallansch LA, et al. Structural

characterization and comparison of promoter activity of mouse and bovine interphotoreceptor retinoid-binding protein (IRBP) gene 5′ flanking regions in WERI, Y79, chick retina cells, and transgenic mice. Curr Eye Res 2001;23(1):20–32.

60.Javahery R, Khachi A, Lo K, Zenzie-Gregory B, Smale ST. DNA sequence requirements for transcriptional initiator activity in mammalian cells. Mol Cell Biol 1994;14(1):116–127.

61.Gonzalez-Fernandez F. Evolution of the visual cycle: the role of retinoid-binding proteins. J Endocrinol 2002;175(1):75–88.

62.Hoegg S, Brinkmann H, Taylor JS, Meyer A. Phylogenetic timing of the fish-specific genome duplication correlates with the diversification of teleost fish. J Mol Evol 2004;59(2):190–203.

63.Force A, Lynch M, Pickett FB, Amores A, Yan YL, Postlethwait J. Preservation of duplicate genes by complementary, degenerative mutations. Genetics 1999;151(4):1531–1545.

64.Postlethwait J, Amores A, Cresko W, Singer A, Yan YL. Subfunction partitioning, the teleost radiation and the annotation of the human genome. Trends Genet 2004;20(10):481–490.

65.Ohno S. Evolution by gene duplication. New York: Springer-Verlag; 1970.

66.Kadonaga JT. Regulation of RNA polymerase II transcription by sequence-specific DNA binding factors. Cell 2004;116(2):247–257.

67.Wray GA, Hahn MW, Abouheif E, Balhoff JP, Pizer M, Rockman MV, et al. The evolution of transcriptional regulation in eukaryotes. Mol Biol Evol 2003;20(9):1377–1419.

68.Kingston RE, Green MR. Modeling eukaryotic transcriptional activation. Curr Biol 1994;4(4):325–332.

69.Pabo CO, Sauer RT. Transcription factors: structural families and principles of DNA recognition. Annu Rev Biochem 1992;61:1053–1095.

70.Boatright JH, Knox BE, Jones KM, Stodulkova E, Nguyen HT, Padove SA, et al. Evidence of a tissue-restricting DNA regulatory element in the mouse IRBP promoter. FEBS Lett 2001;504(1–2):27–30.

71.Boatright JH, Borst DE, Peoples JW, Bruno J, Edwards CL, Si JS, et al. A major cis activator of the IRBP gene contains CRX-binding and Ret-1/PCE-I elements. Mol Vis 1997;3:15.

72.Werner M, Madreperla S, Lieberman P, Adler R. Expression of transfected genes by differentiated, postmitotic neurons and photoreceptors in primary cell cultures. J Neurosci Res 1990;25(1):50–57.

73.Furukawa T, Morrow EM, Cepko CL. Crx, a novel otx-like homeobox gene, shows photoreceptorspecific expression and regulates photoreceptor differentiation. Cell 1997;91(4):531–541.

74.Chen S, Wang QL, Nie Z, Sun H, Lennon G, Copeland NG, et al. Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes. Neuron 1997;19(5):1017–1030.

75.Gumucio DL, Heilstedt-Williamson H, Gray TA, Tarle SA, Shelton DA, Tagle DA, et al. Phylogenetic footprinting reveals a nuclear protein which binds to silencer sequences in the human gamma and epsilon globin genes. Mol Cell Biol 1992;12(11):4919–4929.

76.Liou GI, Matragoon S, Overbeek PA, Fei Y. Identification of a retina-specific footprint within the retina-specific regulatory region of the human interphotoreceptor retinoid-binding protein gene. Biochem Biophys Res Commun 1994;203(3):1875–1881.

77.Boatright JH, Nickerson JM, Borst DE. Site-specific DNA hypomethylation permits expression of the IRBP gene. Brain Res 2000;887(1):211–221.

78.Freund CL, Gregory-Evans CY, Furukawa T, Papaioannou M, Looser J, Ploder L, et al. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 1997;91(4):543–553.

79.Swain PK, Chen S, Wang QL, Affatigato LM, Coats CL, Brady KD, et al. Mutations in the cone-rod homeobox gene are associated with the cone-rod dystrophy photoreceptor degeneration. Neuron 1997;19(6):1329–1336.

80.Borst DE, Si JS, Nickerson JM. Transient expression of IRBP promoter/CAT constructs in retinoblastoma cells. Invest Ophthalmol Vis Sci 1990;31:585, Abstract 2866.

81.Liou GI, Geng L, al-Ubaidi MR, Matragoon S, Hanten G, Baehr W, et al. Tissue-specific expression in transgenic mice directed by the 5′-flanking sequences of the human gene encoding interphotoreceptor retinoid-binding protein. J Biol Chem 1990;265(15):8373–8376.

82.Borst DE, Si JS, Nickerson JM. Functional comparison of the mouse IRBP promoter in Y79 cells and transgenic mice. Invest Ophthalmol Vis Sci 1992;33(4):1399, Abstract 3535.

83.Yokoyama T, Liou GI, Caldwell RB, Overbeek PA. Photoreceptor-specific activity of the human interphotoreceptor retinoid-binding protein (IRBP) promoter in transgenic mice. Exp Eye Res 1992;55(2):225–233.

84.Liou GI, Matragoon S, Yang J, Geng L, Overbeek PA, Ma DP. Retina-specific expression from the IRBP promoter in transgenic mice is conferred by 212 bp of the 5′-flanking region. Biochem Biophys Res Commun 1991;181(1):159–165.

85.Bobola N, Hirsch E, Albini A, Altruda F, Noonan D, Ravazzolo R. A single cis-acting element in a short promoter segment of the gene encoding the interphotoreceptor retinoidbinding protein confers tissue-specific expression. J Biol Chem 1995;270(3):1289–1294.

86.Fei Y, Matragoon S, Smith SB, Overbeek PA, Chen S, Zack DJ, et al. Functional dissection of the promoter of the interphotoreceptor retinoid-binding protein gene: the cone-rod-homeobox element is essential for photoreceptor-specific expression in vivo. J Biochem (Tokyo) 1999;125(6):1189–1199.

87.Boatright JH, Knox BE, Stodulkova E, Nguyen HT, Padove SA, Matheu EA, et al. Tissuerestricting DNA regulatory elements in the mouse IRBP promoter. invest Ophthalmol Vis Sci 2001;42(4):S353, Abstract 1910.

88.Otteson DC, Liu Y, Lai H, Wang C, Gray S, Jain MK, et al. Kruppel-like factor 15, a zincfinger transcriptional regulator, represses the rhodopsin and interphotoreceptor retinoidbinding protein promoters. Invest Ophthalmol Vis Sci 2004;45(8):2522–2530.

89.Otteson DC, Lai H, Liu Y, Zack DJ. Zinc-finger domains of the transcriptional repressor KLF15 bind multiple sites in rhodopsin and IRBP promoters including the CRS-1 and G- rich repressor elements. BMC Mol Biol 2005;6:15.

90.Fong SL, Fong WB. Elements regulating the transcription of human interstitial retinoidbinding protein (IRBP) gene in cultured retinoblastoma cells. Curr Eye Res 1999;18(4): 283–291.

91.Kikuchi T, Raju K, Breitman ML, Shinohara T. The proximal promoter of the mouse arrestin gene directs gene expression in photoreceptor cells and contains an evolutionarily conserved retinal factor-binding site. Mol Cell Biol 1993;13(7):4400–4408.

92.Kimura A, Singh D, Wawrousek EF, Kikuchi M, Nakamura M, Shinohara T. Both PCE- 1/RX and OTX/CRX interactions are necessary for photoreceptor-specific gene expression. J Biol Chem 2000;275(2):1152–1160.

93.Furukauea T, Kozak CA, Cepko CL. rax, a novel paired type homeobox gene, shows expressions in anterior neural fold and developing retuia. Proc Nalt Acad Sci USA 1997;94(7): 3088–3093.

94.Mathers, PH, Grenberg A, Mahon KA, Jamrich M. The Rx homeobox gene is essential for nertekrate eye development. Nature 1997;387(6633):603–607.

95.Akimoto M, Cheng H, Zhu D, Brzezinski JA, Khanna R, Filippova E, et al. Targeting of GFP to newborn rods by Nrl promoter and temporal expression profiling of flow-sorted photoreceptors. Proc Natl Acad Sci U S A 2006;103(10):3890–3895.

96.Mears AJ, Kondo M, Swain PK, Takada Y, Bush RA, Saunders TL, et al. Nrl is required for rod photoreceptor development. Nat Genet 2001;29(4):447–452.

97.Peng GH, Chen S. Chromatin immunoprecipitation identifies photoreceptor transcription factor targets in mouse models of retinal degeneration: new findings and challenges. Vis Neurosci 2005;22(5):575–586.

98.DuBridge RB, Tang P, Hsia HC, Leong PM, Miller JH, Calos MP. Analysis of mutation in human cells by using an Epstein-Barr virus shuttle system. Mol Cell Biol 1987;7(1):379–387.

99.Furukawa T, Morrow EM, Li T, Davis FC, Cepko CL. Retinopathy and attenuated circadian entrainment in Crx-deficient mice. Nat Genet 1999;23(4):466–470.

100.Livesey FJ, Furukawa T, Steffen MA, Church GM, Cepko CL. Microarray analysis of the transcriptional network controlled by the photoreceptor homeobox gene Crx. Curr Biol 2000;10(6):301–310.

101.Bobola N, Briata P, Ilengo C, Rosatto N, Craft C, Corte G, et al. OTX2 homeodomain protein binds a DNA element necessary for interphotoreceptor retinoid binding protein gene expression. Mech Dev 1999;82(1–2):165–169.

102.Boatright JH, Borst DE, Stodulkova E, Nickerson JM. Endogenous CRX expression and IRBP promoter activity in retinoblastoma cells. Brain Res 2001;916(1–2):136–142.

103.Baas D, Bumsted KM, Martinez JA, Vaccarino FM, Wikler KC, Barnstable CJ. The subcellular localization of Otx2 is cell-type specific and developmentally regulated in the mouse retina. Brain Res Mol Brain Res 2000;78(1–2):26–37.

104.Ang SL, Jin O, Rhinn M, Daigle N, Stevenson L, Rossant J. A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. Development 1996;122(1):243–252.

105.Nishida A, Furukawa A, Koike C, Tano Y, Aizawa S, Matsuo I, et al. Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development. Nat Neurosci 2003;6(12):1255–1263.

106.Courtois V, Chatelain G, Han ZY, Le Novere N, Brun G, Lamonerie T. New Otx2 mRNA isoforms expressed in the mouse brain. J Neurochem 2003;84(4):840–853.

107.Arranz V, Dreuillet C, Crisanti P, Tillit J, Kress M, Ernoult-Lange M. The zinc finger transcription factor, MOK2, negatively modulates expression of the interphotoreceptor retin- oid-binding protein gene, IRBP. J Biol Chem 2001;276(15):11963–11969.

108.Livne-Bar I, Pacal M, Cheung MC, Hankin M, Trogadis J, Chen D, et al. Chx10 is required to block photoreceptor differentiation but is dispensable for progenitor proliferation in the postnatal retina. Proc Natl Acad Sci U S A 2006;103(13):4988–4993.

109.Liu IS, Chen JD, Ploder L, Vidgen D, van der Kooy D, Kalnins VI, et al. Developmental expression of a novel murine homeobox gene (Chx10): evidence for roles in determination of the neuroretina and inner nuclear layer. Neuron 1994;13(2):377–393.

110.Dorval KM, Bobechko BP, Ahmad KF, Bremner R. Transcriptional activity of the pairedlike homeodomain proteins Chx10 and VSX1. J Biol Chem 2005;280(11):10100–10108.

111.Rowan S, Cepko CL. Genetic analysis of the homeodomain transcription factor Chx10 in the retina using a novel multifunctional BAC transgenic mouse reporter. Dev Biol 2004;271(2):388–402.

112.Rutherford AD, Dhomen N, Smith HK, Sowden JC. Delayed expression of the Crx gene and photoreceptor development in the Chx10-deficient retina. Invest Ophthalmol Vis Sci 2004;45(2):375–384.

113.Dorval KM, Bobechko BP, Fujieda H, Chen S, Zack DJ, Bremner R. Chx10 targets a subset of photoreceptor genes. J Biol Chem 2006;281(2):744–751.

114.Funk WD, Wright WE. Cyclic amplification and selection of targets for multicomponent complexes: myogenin interacts with factors recognizing binding sites for basic helix-loop- helix, nuclear factor 1, myocyte-specific enhancer-binding factor 2, and COMP1 factor. Proc Natl Acad Sci U S A 1992;89(20):9484–9488.

115.Knoepfler PS, Bergstrom DA, Uetsuki T, Dac-Korytko I, Sun YH, Wright WE, et al. A conserved motif N-terminal to the DNA-binding domains of myogenic bHLH transcription factors mediates cooperative DNA binding with pbx-Meis1/Prep1. Nucleic Acids Res 1999;27(18):3752–3761.

116.Ferretti E, Villaescusa JC, Di Rosa P, Fernandez-Diaz LC, Longobardi E, Mazzieri R, et al. Hypomorphic mutation of the TALE gene Prep1 (pKnox1) causes a major reduction of Pbx and Meis proteins and a pleiotropic embryonic phenotype. Mol Cell Biol 2006;26(15):5650–562.

117.Hisa T, Spence SE, Rachel RA, Fujita M, Nakamura T, Ward JM, et al. Hematopoietic, angiogenic and eye defects in Meis1 mutant animals. EMBO J 2004;23(2):450–459.

118.Zhang X, Friedman A, Heaney S, Purcell P, Maas RL. Meis homeoproteins directly regulate Pax6 during vertebrate lens morphogenesis. Genes Dev 2002;16(16):2097–2107.

119.Wilson D, Sheng G, Lecuit T, Dostatni N, Desplan C. Cooperative dimerization of paired class homeo domains on DNA. Genes Dev 1993;7(11):2120–2134.

120.Mathers PH, Grinberg A, Mahon KA, Jamrich M. The Rx homeobox gene is essential for vertebrate eye development. Nature 1997;387(6633):603–607.

121.Nickerson JM, Frey RA, Ciavatta VT, Stenkamp DL. Interphotoreceptor retinoid-binding protein gene structure in tetrapods and teleost fish. Mol Vis 2006;12:1565–1585.