BL A582 Graduate Seminar in CMR (Cell Molecular Regulation) Fall 1999, Dr.Stark

An introduction for the topic selected for Fall, 1999, Visual Development

Since classic studies (Spemann 1938), the vertebrate eye has been a modelfor demonstrating induction in development. Much later, but nearly a quarter of a century ago, Ready et al. (Ready, Hanson and Benzer 1976) initiated a productive line of research which came to establish the intracellular signaling mechanisms (such as the sevenless signaling cascade) responsible for establishing cellular identity. As molecular biology came of age, some amazingly rapid progress made the development of the retina in both invertebrates a model for many aspects of gene control.

The purpose of the selection of the topic of visual development for this semester's graduate seminar in CMR (cell and molecular regulation) will be to explore recent advances in understanding cellular development and gene control. As I perused my notes from vision, Drosophila, and visual development meetings, I am overwhelmed with the vastness of this field. Thus, it is important for me to delimit the purpose of this introductory paper and my introductory lecture material. Here I present only a few of the major thrusts in this field and give you target references in a waythat you can easily explore some abstracts and on-line papers on the internet using the PubMed hyperlinks I just showed you. Using that as a springboard, I can help you to find and define topics you select to develop for presentation. Also, I may have (paper) copies of some of the papers you find to lend you.

In holometabolous insects, groups of cells are set aside in the larva which are determined to become structures of the adult (imago), and these arecalled imaginal disks. Don Ready (Slide) working in Seymour Benzer's lab at Caltech pioneered the current research on how the adult eye develops from the previously undifferentiated tissue (Ready, Hanson and Benzer 1976). The Drosophila compound eye is composed of about 800 ommatidia with a precise array of about 20 cells (Slide, Yama). Since that time, the sevenless signaling cascade, involving Ras (Slide, Yama2), has become one of the most famous of signaling cascades and is the subject of much research and many reviews,for instance (Yamamoto 1994). All of the cells of each ommatidium are assembled in a step-wise factor (Slide, Cagan) (Van Vactor et al. 1991). In 1998, I taught BL A512 "Signal Transduction" as a lecture course and prepared a lecture on "Development in the Drosophila eye; "the outline for this lecture may prove useful for review of this topic. Such cascades are widely used, and, even in Drosophila eye development, they go beyond just "bride of sevenless" as the ligand and "sevenless" as the receptor tyrosine kinase (Slide, Moses3) (Tio and Moses 1997).

A fundamental aspect of signaling cascades such as the sevenless signaling cascade is that they go from the membrane to regulation of genes. Thus there is considerable work on transcription factors in Drosophila eye development since a review by Kevin Moses (Slides, Moses1&2) (Moses 1991). Factors are proteins which bind to DNA elements, and one of the major examples is steroid hormone (and retinoic acid) receptor binding to the corresponding hormone response elements. An introductory outline on this topic is in my signal transduction course. I offer you here a paper in an online journal (Molecular Vision) on response factors and transcription factors in the rat retina (He et al., 1998) and another paper on factor binding and response elements for IRBP (Boatright et al. 1997). I have not been able to find much work on control of eye development by traditional hormones, but here is one (Champlin and Truman 1998).


How the morphogenetic furrow progresses has been the subject of much research. Hedgehog (hh) and decapentaplegic (dpp) have been known to be involved in the progression of the morphogenetic furrow. A recent review (Treisman and Heberlein 1998) this mechanism as well as the interaction with wingless (wg). This paper also briefly reviews the determination of the eye primordium by eyeless and other genes, proneural genes (atonal and daughterless), antineural genes (hairy and extramacrochaetae), and control of mitosis. Here is an outline from my signaltransduction course which includes coverage of hedgehog and one of its vertebrate homologues, sonic hedgehog.

Sonic hedgehog has been implicated in vertebrate visual development. Cyclopiais induced by alkaloids from Veratrum californicum, inhibitors of cholesterol synthesis; although the Hedgehog signaling molecule is covalently modified by cholesterol, this phenomenon is perhaps via interacting with the Patched protein in the Shh pathway (Cooper et al. 1998; Strauss 1998). For those of you who attended the department's seminar series Fall, 1998,the topic of cyclopia may sound familiar: Yi Rao from Wash U gave a seminar on his very recent work (sorry, no citations of his work yet) on holoprosencephaly and the early control of the development of 2 eyes from 1 primordium.

Research on the promoter for opsin's gene began in Drosophila when Mismer& Rubin (Mismer and Rubin 1987) found common promoter sequences like RCS I (Rhodopsin Core Sequence) (Fortini and Rubin 1990).A frequently replicated finding is that a short ["proximal"] promoter segment drives photoreceptor cell-specific expression via conserved response elements (REs) such as Ret-1/PCE-1 (Photoreceptor Conserved Element, = RCSI) which has recently been shown to bind several known and novel proteins (Kimura, Nakanura and Shinohara 1998). Techniques such as gel mobility shifts and DNase I footprinting are defining these DNA sequences and their corresponding transcription factors (Ahmad, 1995; DesJardin and Hauswirth 1996; DiPolo, Bowes Rickman and Farber 1996; Morabito, Yu and Barnstable 1991). For instance, transcription factors are being identified on the basisof 3 footprints in the rod transducin a subunit (Fong and Fong 1998). Also, DNaseI footprinting and gel shifts helped to identify several REs in the proximal promoters of the human X-linked red and green opsin genes expressed in WERI retinoblastoma cells (Shaaban and Deeb 1998).

A fundamental finding of common mechanisms of eye development was announced in 1994 by Gehring and coworkers (Quiring et al. 1994); genes with paired boxes (Pax) are involved in early eye determination in Drosophila (ey), mouse (Small eye) and humans (Aniridia). This is remarkable since diverse eyes are thought to have evolved separately. This announcement was so fundamental that it generated lots of further work which quickly generated integrative reviews (Macdonald and Wilson 1996). Desplan and co-workers think that the general control stems from Pax-6/eyelesscontrolling eye genes like rhodopsin (Sheng et al. 1997). Now it is known that eyeless initiates expression of two other early eye genes, sine oculis and eyes absent (Halder et al. 1998). Pax 6 interacts with TATA-box-binding protein (Cvekl et al. 1999). Many aspects of these interesting issues in visual development have been the subject of recent reviews and integrative commentary, for instance from Desplan (Desplan 1997).
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Eya has been the subject of considerable recent work in Drosophila (Bonini, Leiserson and Benzer 1998) since the discovery of its involvement in programmed cell death (apoptosis) (Bonini, Leiserson and Benzer 1993). There is a substantial literature on apoptosis in vertebrate retinal degenerations, and here is an article to get you started (Papermaster and Windle 1995). It was shown that Eya protein complexes with proteins of So (Pignoni et al. 1997) and Daschund (Chen et al. 1997) in eye development in Drosophila. You can find an introductory outline of apoptosis in my signal transduction course

Because of its advantages for visual development, Drosophila dominated earlier studies. As molecular biology matured, vertebrate visual development has been studied extensively mostly from the standpoint of human disease (Morrow, Furukawa and Cepko 1998). Much of the disease work is not really related to development but rather to the G-protein signal cascade which starts with rhodopsin. Now there is a web site where information relevant to the retina, especially genetic causes of blindness, accumulates (site).Here is an outline from my visual transduction course related to molecular genetics of blindness in humans.

Pax 6 interacts with TATA-box-binding protein (Cvekl et al. 1999). There are many mammalian homologues of Drosophila genes, for instance Six3 for sine oculis (Loosli et al. 1998), murine otx for Drosophila Otd (orthodenticle, related to ocelliless) (Acampora et al. 1998), and Notch (Ahmad, Zagouras and Artavanis-Tsakonas 1995). Yes, Notch, that ubiquitous neurogenic gene, is involved in visual development in Drosophila and it interacts with other important genes (Sawamoto and Okano 1996).

Mutations in the cone-rod-homeobox gene (CRX) gene cause human cone-rod dystrophies (Freund et al. 1997; Swain et al. 1997);CRX codes for a paired-like homeodomain protein and is related to Drosophilaotd and mouse otx which partially rescue ocelliless [ocelli are simple eyes]mutations in Drosophila (Nagao et al. 1998). In Oct., 1999, the department's seminar series will feature Shiming Chen from Wash U whose work addresses CRX and retinal dystrophies such as Leber congenital amaurosis (Swaroop et al. 1999). Homeobox gene expression was found in the embryonic chicken retina (Dhawan, Schoen and Beebe 1997). (David Beebe was one of our seminar speakers last year (Spring, 1999, "The lens as an organizer of eye development").) These latter findings integrate current work on development and human disease.

It was found that a clone of daughter cells from a single progenitor in Xenopus was distributed in a "column," (across layers) (Slide);cells were marked with horseradish peroxidase (Holt et al. 1988). Later, such cell lineages were determined by marking cells with retroviral vectors (Cepko et al. 1998). In rats, half of the retinal cells are born postnatally. Rods are born throughout retinal development and peak in the middle time. Ganglion cells are born first, and cones and amacrine cells are born early. Bipolars and Muller cells are born late. These birth dates of various cell types in the vertebrate retina were determined with tritiated thymidine labeling (Young 1985). Here is a paper for those interested in cyclin (and control of mitosis) in retinal degeneration / development (Ma, Papermaster and Cepko 1998). For any of you interested in growth factors and similar molecules, there is some literature on how they protect against retinal degeneration, and here is an article to get you started (LaVail et al. 1998)

 

The fish has become a model for retinal development because there is a very stereotyped organization of rods and cones referred to as a "mosaic." Also, development continues through adult life at the edge of the retina. Such development of rods and cones in goldfish are described in several papers, for instance (Stenkamp, Barthel and Raymond 1997). In Xenopus, the ciliary margin zone is renewed and proliferates and expresses neurogenic and proneural genes in a spatially tidy array (Perron et al.1998). Although the lower vertebrates have advantages, there are descriptive studies of development of connections in the monkey retina (Hendrickson 1996)

Regulation of the genes for human red and green visual pigments is a veryspecial case. It is now clear that unequal crossing over the course of the re-evolution of trichromatic color vision in primates has made itso that most "color normal" individuals may have many copies of these genes in tandem on the X chromosome. Appropriate regulation of expression of one "red gene" and one "green gene" relies not only on traditional promoters but also on a LCR (locus control region) way upstream (Slide) (Bowmaker 1998b) see also (Bowmaker 1998a)

Well, that's certainly not comprehensive, but it's (more than) enough toget you started. Have fun!

References:

Acampora, D., V. Avantaggiato, F. Tuorto, P. Barone, H. Reichert, R. Finkelstein, and A. Simeone, 1998 Murine Otx1 and Drosophila otd genes share conserved genetic functions required in invertebrate and vertebrate brain development. Development. 125: 1691-702.

Ahmad, I., 1995 Mash-1 is expressed during rod photoreceptor differentiationand binds an E-box, Eopsin-1 in the rat opsin gene. Develop. Brain Res.90: 184-189.

Ahmad, I., P. Zagouras, and S. Artavanis-Tsakonas, 1995 Involvement of Notch-1 in mammalian neurogenesis: association of Notch-1 activity with both immature and terminally differentiated cells. Mech. Develop. 53: 73-85.

Boatright, J. H., D. E. Borst, J. W. Peoples, J. Bruno, C. L. Edwards, J.S. Si and J. M. Nickerson, 1997 A Major Cis Activator of the IRBP Gene containsCRX-binding and Ret-1/PCE-I elements. Mol. Vis. 3: 15.

Bonini, N. M., W. M. Leiserson and S. Benzer, 1993 The eyes absent gene:genetic control of cell survival and differentiation in the developing Drosophilaeye. Cell 72: 379-395.

Bonini, N. M., W. M. Leiserson and S. Benzer, 1998 Multiple roles of theeyes absent gene in Drosophila. Dev. Biol. 196: 42-57.

Bowmaker, J. K., 1998a Evolution of colour vision in vertebrates. Eye 12:541-547.

Bowmaker, J. K., 1998b Visual Pigments and molecular genetics of color blindness.News Physiol. Sci. 13: 63-69.

Cepko, C. L., S. Fields-Berry, E. Ryder, C. Austin and J. Golden, 1998 Lineageanalysis using retroviral vectors. Curr Top Dev Biol 36: 51-74.

Champlin, D. T., and J. W. Truman, 1998 Ecdysteroids govern two phases of eye development during metamorphosis of the moth, Manduca sexta. Development. 125: 2009-18.

Chen, R., M. Amoui, Z. Zhang and G. Mardon, 1997 Dachshund and eyes absentproteins form a complex and function synergistically to induce ectopic eyedevelopment in Drosophila. Cell 91: 893-903.

Cooper, M. K., J. A. Porter, K. E. Young and P. A. Beachy, 1998 Teratogen-mediatedinhibition of target tissue response to Shh signalling. Science 280: 1603-1607.

Cvekl, A., F. Kashanchi, J. N. Brady, and J. Piatigorsky, 1999 Pax-6 interactions with TATA-box-binding protein and retinoblastoma protein. Invest Ophthalmol Vis Sci. 40: 1343-50.

DesJardin, L. E., and W. W. Hauswirth, 1996 Developmentally important DNAelements within the bovine opsin upstream region. Invest. Ophthalmol. Vis.Sci. 37: 154-165.

Desplan, C., 1997 Eye development: governed by a dictator or a junta? (Minireview).Cell 26: 861-864.

Dhawan, R. R., T. J. Schoen and D. C. Beebe, 1997 Isolation and Expressionof Homeobox Genes from the Embryonic Chicken Eye. Mol. Vis. 3: 7.

Di Polo, A., C. Bowes Rickman and D. B. Farber, 1996 Isolation and initialcharacterization of the 5' flanking region of the human and murine cyclicguanosine monophosphate-phosphodiesterase b-subunit genes. Invest. Ophthalmol.Vis. Sci. 37: 551-560.

Fong, S. L., and W. B. Fong, 1998 Chracterization of the promoter regionof human rod transducin a-subunit (GNAT1) gene. Invest. Ophthalmol. Vis.Sci. Suppl. 39: S675.

Fortini, M. E., and G. M. Rubin, 1990 Analysis of cis-acting requirementsof the Rh3 and Rh4 genes reveals a bipartite organization to rhodopsin promotersin Drosophila melanogaster. Genes Dev. 4: 444-463.

Freund, C. L., C. Y. Gregory-Evans, T. Furukawa, M. Papaiooannou, J. Looser,L. Ploder, J. Bellingham, D. Ng, J.-A. S. Herbrick, A. Duncan, S. W. Scherer,L. C. Tsui, A. Loutradis-Anagnostou, S. G. Jacobson, C. L. Cepko, S. Bhattacharyaand R. R. McInnes, 1997 Cone-rod dystrophy due to mutations in a novel photoreceptor-specifichomeobox gene (CRX) essential for the maintenance of the photoreceptor.Cell 91: 543-553.

Halder, G., P. Callaerts, S. Flister, U. Waldorf, U. Kloter and G. W. J.,1998 Eyeless initiates the expression of both sine oculis and eyes absentduring Drosophila eye development. Development 125: 2181-2191.

He, L., M. L. Campbell, D. Srivastava, Y. S. Blocker, J. R. Harris, A. Swaroopand D. A. Fox, 1998 Spatial and Temporal Expression of AP-1 Responsive RodPhotoreceptor Genes and bZIP Transcription Factors During Development ofthe Rat Retina. Mol. Vis 4: 32.

Hendrickson, A. E., 1996 Synaptic development in macaque monkey retina andits implications for other developmental sequences. Perspect. Dev. Neurobiol.3: 195-201.

Holt, C. E., T. W. Bertsch, H. M. Ellis and W. A. Harris, 1988 Cellulardetermination in the Xenopus retina is independent of lineage and birthdate. Neuron 1: 15-26.

Kimura, A., M. Nakanura and T. Shinohara, 1998 Isolation and characterizationof regulatory factors bind to the PCE1 site of the arrestin promoter. Invest.Ophthalmol. Vis. Sci. Suppl. 39: S47.

LaVail, M. M., D. Yasumura, M. T. Matthes, C. Lau-Villacorta, K. Unoki, C. H. Sung, and R. H. Steinberg, 1998 Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci. 39: 592-602.

Loosli, F., K. s. RW, M. Carl, A. Krone, and J. Wittbrodt, 1998 Six3, a medaka homologue of the Drosophila homeobox gene sine oculis is expressed in the anterior embryonic shield and the developing eye. Mech Dev. 74: 159-64.

Ma, C., D. Papermaster, and C. L. Cepko, 1998 A unique pattern of photoreceptor degeneration in cyclin D1 mutant mice. Proc Natl Acad Sci U S A. 95: 9938-43.

Macdonald, R., and S. W. Wilson, 1996 Pax proteins and eye development.Curr. Opin. Neurobiol. 6: 49-56.

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Morabito, M. A., X. Yu and C. J. Barnstable, 1991 Characterization of developmentallyregulated and retina-specific nuclear protein binding to a site in the upstreamregion of the rat opsin gene. J. Biol. Chem. 266: 9667-9673.

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Nagao, T., S. Leuzinger, D. Acampora, A. Simeone, R. Finkelstein, H. Reichertand K. Furukubo-Tokunaga, 1998 Developmental rescue of Drosophila cephalicdefects by the human Otx genes. Proc. Nat. Acad. Sci. USA 95: 3737-3742.

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Perron, M., S. Kanekar, M. L. Vetter and W. A. Harris, 1998 The geneticsequence of retinal development in the ciliary margin of the Xenopus eye.Dev. Biol. 199: 185-200.

Pignoni, F., B. Hu, K. H. Zavitz, J. Xiao, P. A. Garrity and S. L. Zipursky,1997 The eye-specific proteins So and Eya form a complex and regulate multiple steps in Drosophila eye development. Cell 91: 881-891.

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Shaaban, S. A., and S. S. Deeb, 1998 Functional analysis of the promoters of the human red and green visual pigment genes. Invest. Ophthalmol. Vis.Sci. 39: 885-896.

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This page last revised on September 9, 1999