Review Article
Full Access
Lens development and crystallin gene expression: many roles for Pax-6
Aleš Cvekl,
Joram Piatigorsky,
Aleš Cvekl
Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892–2730, USA.
Search for more papers by this authorJoram Piatigorsky
Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892–2730, USA.
Search for more papers by this authorAleš Cvekl,
Joram Piatigorsky,
Aleš Cvekl
Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892–2730, USA.
Search for more papers by this authorJoram Piatigorsky
Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892–2730, USA.
Search for more papers by this authorAbstract
The vertebrate eye lens has been used extensively as a model for developmental processes such as determination, embryonic induction, cellular differentiation, transdifferentiation and regeneration, with the crystallin genes being a prime example of developmentally controlled, tissue-preferred gene expression. Recent studies have shown that Pax-6, a transcription factor containing both a paired domain and homeodomain, is a key protein regulating lens determination and crystallin gene expression in the lens. The use of Pax-6 for expression of different crystallin genes provides a new link at the developmental and transcriptional level among the diverse crystallins and may lead to new insights into their evolutionary recruitment as refractive proteins.
References
- 1 Saha, M. S., Servetnick, M. and Grainger, R. M. (1992). Vertebrate eye development. Curr. Opin. Genet. Dev. 2, 582–588.
- 2 Grainger, R. M. (1992). Embryonic lens induction: shedding light on vertebrate tissue determination. Trends Genet. 8, 349–355.
- 3 Wistow, G. J. and Piatigorsky, J. (1988). Lens crystallins: the evolution and expression of proteins for a highly specialized tissue. Annu. Rev. Biochem. 57, 479–504.
- 4 Hill, R. E. et al. (1991). Mouse Small eye results from mutations in a paired-like homeobox-containing gene. Nature 354, 522–525.
- 5 Krauss, S., Johansen, T., Korzh, V. and Fjose, A. (1991). Zebrafish pax[zf-a]: a paired box-containing gene expressed in the neural tube. EMBO J. 10, 3609–3619.
- 6 Ton, C. C. et al. (1991). Positional cloning and characterization of a paired box-and homeobox-containing gene from the aniridia region. Cell 67, 1059–1074.
- 7 Walther, C. and Gruss, P. (1991). Pax-6, a murine paired box gene, is expressed in the developing CNS. Development 113, 1435–1449.
- 8 Glaser, T., Walton, D. S. and Maas, R. L. (1992). Genomic structure, evolutionary conservation and aniridia mutations in the human Pax6 gene. Nature Genet. 2, 232–239.
- 9 Quiring, R., Walldorf, U., Kloter, U. and Gehring, W. J. (1994). Homology of the eyeless gene of Drosophila to the Small eye gene in mice and aniridia in humans. Science 265, 785–789.
- 10 Halder, G., Callaerts, P. and Gehring, W. J. (1995). Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science 267, 1788–1792.
- 11 Beebe, D. C. (1994). Homeobox genes and vertebrate eye development. Invest. Ophthal. Vis. Sci. 35, 2897–2900.
- 12 Dressler, G. R., Deutsch, U., Chowdhury, K., Nornes, H. O. and Gruss, P. (1990). Pax2, a new murine paired-box-containing gene and its expression in the developing excretory system. Development 109, 787–795.
- 13 Macdonald, R. et al. (1995). Midline signalling is required for Pax gene regulation and patterning of the eyes. Development 121, 3267–3278.
- 14 Macdonald, R., Barth, K. A., Xu, Q., Holder, N., Mikkola, I. and Wilson, S. W. (1994). Regulatory gene expression boundaries demarcate sites of neuronal differentiation in the embryonic zebrafish forebrain. Neuron 13, 1039–1053.
- 15 Simeone, A. et al. (1993). A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo. EMBO J. 12, 2735–2747.
- 16 Matsuo, I., Kuratani, S., Kimura, C., Takeda, N. and Aizawa, S. (1995). Mouse Otx2 functions in the formation and patterning of rostral head. Genes Dev. 9, 2646–2658.
- 17 Acampora, D. et al. 1995. Forebrain and midbrain regions are deleted in Otx2−/- mutants due to a defective anterior neuroectoderm specification during gastrulation. Development 121, 3279–3290.
- 18 Monaghan, A. P. et al. (1991). The Msh-like homeobox genes define domains in the developing vertebrate eye. Development 112, 1053–1061.
- 19 Oliver, G., Sosa-Pineda, B., Geisendorf, S., Spana, E. P., Doe, C. Q. and Gruss, P. (1993). Prox-1, a prospero-related homeobox gene expressed during mouse development. Mech. Dev. 44, 3–16.
- 20 Tomarev, S. I., Sundin, O., Banerjee-Basu, S., Duncan, M. K., Yang, J.-M. and Piatigorsky, J. (1996). A chicken homeobox gene Prox1 related to Drosophila Prospero is expressed in the developing lens. Dev. Dynam. (in press).
- 21 Taira, M., Hayes, W. P., Otani, H. and Dawid, I. B. (1993). Expression of LIM class homeobox gene Xlim-3 in Xenopus development is limited to neural and neuroendocrine tissues. Dev. Biol. 159, 245–259.
- 22 Lieu, I. S. C. et al. (1994). Developmental expression of a novel murine homeobox gene (CHx 10): evidence for roles in determination of the neuroretina and inner nuclear layer. Neuron 13, 377–393.
- 23 Simeone, A., Gulisano, M., Acampora, D., Stornaiulo, A., Rambaldi, M. and Boncinelli, E. (1992). Two vertebrate homeobox genes related to the Drosophila empty spiracles gene are expressed in the embryonic cerebral cortex. EMBO J. 11, 2541–2550.
- 24 Oliver, G., Mailhos, A., Wehr, R., Copeland, N. G., Jenkins, N. A. and Gruss, P. (1995). Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural tube and is expressed during eye development. Development 121, 4045–4055.
- 25 Sundin, O., Toy, J., Leppert, G., Yang, J.-M. and Kang, R. (1996). Optx: a novel family of homeobox genes selectively expressed in the developing eye. Invest. Ophthal. Vis. Sci. 37 (Suppl.), 200.
- 26 Hodgkinson, C. 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.
- 27 Hatini, V., Tao, W. and Lai, E. (1994). Expression of winged helix genes, BF-1 and BF-2, define adjacent domains within the developing forebrain and retina. J. Neurobiol. 25, 1239–1309.
- 28 Wang, S.-Z. and Adler, R. (1994). A developmentally regulated basic-leucine zipper-like gene and its expression in embryonic retina and lens. Proc. Natl Acad. Sci. USA 91, 1351–1355.
- 29 Dolle, P., Rubeete, E., Leroy, P., Morris-Kay, G. and Chambon, P. (1990). Retinoic acid receptors and cellular retinoid binding proteins. I Systematic study of their differential pattern of transcription during mouse organogenesis. Development 110, 1133–1151.
- 30 Dolle, P., Fraulob, V., Kastner, P. and Chambon, P. (1994). Developmental expression of murine retinoid X receptor (RXR) genes. Mech. Dev. 45, 91–104.
- 31 Kamachi, Y., Sockanathaw, S., Liu, Q., Breitman, M., Lovell-Badge, R. and Kondoh, H. (1995). Involvement of SOX proteins in lens-specific activation of crystallin genes. EMBO J. 14, 3510–3519.
- 32 Martin, P. et al. 1992. Characterization of a paired box- and homeobox-containing quail gene (Pax-QNR) expressed in the neuroretina. Oncogene 7, 1721–1728.
- 33 Hanson, I. et al. (1994). Mutations at the PAX6 locuss are found in heterogenous anterior segment malformations including Peter's anomaly. Nature Genet. 6, 168–173.
- 34 Glaser, T., Jepeal, L., Edwards, J. G., Young, S. R., Favor, J. and Maas, R. L. (1994). PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nature Genet. 8, 463–471.
- 35 Grindley, J. C., Davidson, D. R. and Hill, R. E. (1995). The role of Pax-6 in eye and nasal development. Development 121, 1433–1442.
- 36 Li, H.-S., Yang, J.-M., Jacobson, R. D., Pasko, D. and Sundin, O. (1994). Pax-6 is first expressed in a region of ectoderm anterior to the early neural plate: implications for stepwise determination of the lens. Dev. Biol. 162, 181–194.
- 37 Fujiwara, M., Uchida, T., Osumi-Yamashita, N. and Eto, K. (1994). Uchida rat (rSey): a new mutant rat with craniofocal abnormalities resembling those of the mouse Small eye mutant. Differentiation 57, 31–38.
- 38 Quinn, J. C., West, J. D. and Hill, R. E. (1996). Multiple functions for Pax6 in mouse eye and nasal development. Genes Dev. 10, 435–446.
- 39 Kastner, P. et al. (1994). Genetic analysis of RXRa' developmental function: convergence of RXR and RAR signalling pathways in heart and eye morphogenesis. Cell 78, 987–1003.
- 40 Lohnes, D. et al. (1994). Function of the retinoic acid receptors (RARs) during development. (1) Craniofacial and skeletal abnormalities in RAR double mutants. Development 120, 2723–2748.
- 41 Plaza, S., Dozier, C. and Saule, S. (1993). Quail PAX-6 (PAX-QNR) encodes a transcription factor able to bind and transactivate its own promoter. Cell Growth Differ. 4, 1041–1050.
- 42 Treisman, J., Harris, E. and Desplan, C. (1991). The paired box encodes a second DNA-binding domain in the Paired homeo domain protein. Genes Dev. 5, 594–604.
- 43 Treisman, J., Gonczy, P., Vashishtha, M., Harris, E. and Desplan, C. (1989). A single amino acid can determine the DNA binding specificity of homeodomain proteins. Cell 59, 553–562.
- 44 Xu, W., Rould, M. A., Jun, S., Desplan, C. and Pabo, C. (1995). Crystal structure of a paired domain-DNA complex at 2.5A resolution reveals structural basis for Pax developmental mutations. Cell 80, 639–650.
- 45 Epstein, J. A., Glaser, T., Cai, L., Jepeal, L., Walton, D. S. and Maas, R. L. (1994). Two independent and interactive DNA-binding subdomains of the Pax6 paired domain are regulated by alternative splicing. Genes Dev. 8, 2022–2034.
- 46 Epstein, J., Cai, J., Glaser, T., Jepeal, L. and Maas, R. L. (1994). Identification of a Pax paired domain recognition sequence and evidence for DNA-dependent conformational change. J. Biol. Chem. 269, 8355–8361.
- 47 Czerny, T., Schaffner, G. and Busslinger, M. (1993). DNA sequence recognition structure of the paired domain and its binding site. Genes Dev. 7, 2048–2061.
- 48 Czerny, T. and Busslinger, M. (1995). DNA-binding and transactivation properties of Pax-6: three amino acids in the paired domain are responsible for the different sequence recognition of Pax-6 and BSAP (Pax-5). Mol. Cell. Biol. 15, 2858–2871.
- 49 Carriere, C. et al. 1995. Nuclear localization signals, DNA binding, and transactivation properties of quail Pax-6 (Pax-QNR) isoforms. Cell Growth Diff. 6, 1531–1540.
- 50 Carriere, C. S. et al. (1993). Characterization of quail Pax-6 (Pax-QNR) proteins expressed in the neuroretina. Mol. Cell. Biol. 13, 7257–7266.
- 51 Cvekl, A., Sax, C. M., Bresnick, E. H. and Piatigorsky, J. (1994). Complex array of positive and negative elements regulates the chicken αA-crystallin gene: involvement of Pax-6, USF, CREB and/or CREM, and AP-1 proteins. Mol. Cell. Biol. 14, 7363–7367.
- 52 Cvekl, A., Kashanchi, F., Sax, C. M., Brady, J. and Piatigorsky, J. (1995). Transcriptional regulation of the mouse αA-crystallin gene: activation dependent on a cyclic AMP-responsive element (DE1/CRE) and a Pax-6-binding site. Mol. Cell. Biol. 15, 653–660.
- 53 Cvekl, A., Sax, C. M., Li, X., McDermott, J. B. and Piatigorsky, J. (1995). Pax-6 and lens-specific transcription of the chicken δ1-crystallin gene. Proc. Natl Acad. Sci. USA 92, 4681–4685.
- 54 Richardson, J., Cvekl, A. and Wistow, G. (1995). Pax-6 is essential for lens-specific expression of α-crystallin. Proc. Natl Acad. Sci. USA 92, 4676–4680.
- 55 Piatigorsky, J. and Zelenka, P. S. (1992). Transcriptional regulation of crystallin genes: cis elements, trans-factors, and signal transduction systems in the lens. Adv. Dev. Biochem. 1, 211–256.
- 56 Piatigorsky, J. (1992). Lens crystallins. Innovation associated with changes in gene regulation. J. Biol. Chem. 267, 4277–4280.
- 57 Sax, C. M. and Piatigorsky, J. (1994). Expression of the α-crystallin/small heat shock protein/molecular chaperone genes in the lens and other tissues. Adv. Enzymol. Relat. Areas Mol. Biol. 69, 155–201.
- 58 Tomarev, S. I. and Piatigorsky, J. (1996). Lens crystallins of invertebrates: recruitment from glutathione S-transferase, aldehyde dehydrogenase and other novel proteins. Eur. J. Biochem. 235, 449–465.
- 59 Haynes, J. I., II, Duncan, M. K. and Piatigorsky, J. (1996). Spatial and temporal activity of the αB-crystallin/small heat shock protein gene promoter in transgenic mice. Dev. Dynam. (in press).
- 60 Goring, D. R., Bryce, D. M., Tsui, L.-C., Breitman, M. L. and Liu, Q. (1993). Developmental regulation and cell type-specific expression of the murine γF-crystallin gene is mediated through a lens-specific element containing the γF-1 binding site. Dev. Dynam. 196, 143–152.
- 61 Duncan, M. K., Li, X., Ogino, H., Yasuda, K. and Piatigorsky, J. (1996). Developmental regulation of the chicken βB1-crystallin promoter in transgenic mice. Mech. Dev. (in press).
- 62 McDermott, J. B., Cvekl, A. and Piatigorsky, J. (1996). Lens-specific expression of a chicken βA3/A1-crystallin promoter fragment in transgenic mice. Biochem. Biophys. Res. Commun. 221, 559–564.
- 63 Dirks, R. P. H., Klok, E. J., van Genesen, S. T., Schoenmakers, J. G. G. and Lubsen, N. H. (1996). The sequence of regulatory events controlling the expression of the γD-crystallin gene during fibroblast growth factor-mediated rat lens fiber differentiation. Dev. Biol. 173, 14–25.
- 64 Sax, C. M. et al. (1995). Lens-specific activity of the mouse αA-crystallin promoter in the absence of TATA box: functional and protein binding analysis of the mouse αA-crystallin PE1 region. Nucleic Acids Res. 23, 442–451.
- 65 Gopal-Srivastava, R., Haynes, J. I., II, and Piatigorsky, J. (1995). Regulation of the murine αB-crystallin/small heat shock protein gene in cardiac muscle. Mol. Cell. Biol. 15, 7081–7090.
- 66 Sekido, R. et al. (1994). The δ-crystallin enhancer-binding protein δEF1 is a repressor of E2-box-mediated gene activation. Mol. Cell. Biol. 14, 5692–5700.
- 67 Liu, Q., Shalaby, F., Puri, M. C., Tang, S. and Breitman, M. L. (1994). Novel zinc finger proteins that interact with the mouse γF-crystallin promoter and are expressed in the sclerotome during early somitogenesis. Dev. Biol. 165, 165–177.
- 68 Tini, M., Fraser, R. A. and Giguere, V. (1995). Functional interactions between retinoic acid receptor-related orphan nuclear receptor (RORα) and the retinoic acid receptors in the regulation of the γF-crystallin gene. J. Biol. Chem. 270, 20156–20161.
- 69 Matsuo, I. and Yasuda, K. (1992). The cooperative interaction between two motifs of an enhancer element of the chicken αA-crystallin gene, αCE1 and αCE2, confers lens-specific expression. Nucleic Acids Res. 20, 3701–3712.
- 70 Frederikse, P. F. and Piatigorsky, J. (1994). Normal and heat-inducible binding of HSF proteins to α-crystallin regulatory sequences. Invest. Ophthalmol. Visual. Sci. 35 (Suppl.), 2073.
- 71 Pituello, F., Yamada, G. and Gruss, P. (1995). Activin A inhibits Pax-6 expression and perturbs cell differentiation in the developing spinal cord in vitro. Proc. Natl Acad. Sci. USA 92, 6952–6956.
- 72 Ekker, S. C. et al. (1995). Patterning activities of vertebrate hedgehog proteins in the developing eye and brain. Curr. Biol. 5, 944–955.
