Molecular Mechanisms of Optic Vesicle Development: Complexities, Ambiguities and Controversies ⁎ Ruben Adler A,B, , M

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Developmental Biology 305 (2007) 1–13 www.elsevier.com/locate/ydbio

Review Molecular mechanisms of optic vesicle development: Complexities, ambiguities and controversies ⁎ Ruben Adler a,b, , M. Valeria Canto-Soler a

a Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA b Department of Neuroscience, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA Received for publication 22 December 2006; revised 26 January 2007; accepted 30 January 2007 Available online 7 February 2007

Abstract

Optic vesicle formation, transformation into an optic cup and integration with neighboring tissues are essential for normal eye formation, and involve the coordinated occurrence of complex cellular and molecular events. Perhaps not surprisingly, these complex phenomena have provided fertile ground for controversial and even contradictory results and conclusions. After presenting an overview of current knowledge of optic vesicle development, we will address conceptual and methodological issues that complicate research in this field. This will be done through a review of the pertinent literature, as well as by drawing on our own experience, gathered through recent studies of both intra- and extra-cellular regulation of optic vesicle development and patterning. Finally, and without attempting to be exhaustive, we will point out some important aspects of optic vesicle development that have not yet received enough attention. © 2007 Elsevier Inc. All rights reserved.

Keywords: Epigenetic mechanisms; Extracellular signaling molecules; Eye development; Morphogenetic mechanisms; Lens induction; Optic cup; Optic vesicle; Pattern formation; Retina development; Retinal pigment epithelium; Transcription factors

Introduction Comprehensive reviews of the studies done before the year 2000 are available (e.g., Chow and Lang, 2001; Jean et al., This article will present an overview of the complex cellular 1998; Zhang et al., 2002; Lupo et al., 2000) and more recent and molecular mechanisms underlying the formation of the contributions have been partially reviewed (e.g., Bailey et al., optic vesicle (OV), the interactions of the OV with neighbor- 2004; Esteve and Bovolenta, 2006; Lovicu and McAvoy, ing tissues, and its transformation into an optic cup (OC) 2005; Lupo et al., 2006; Sullivan et al., 2004; Wilson and containing three different but interconnected domains (neural Houart, 2004; Yang, 2004; Zaghloul et al., 2005, among retina, retinal pigment epithelium and optic stalk). These others). We will only present here a brief summary of this phenomena have attracted much attention since the early days material, as background for a discussion of problems of of experimental embryology but, despite considerable pro- experimental design and interpretation that are at least partially gress, they remain incompletely understood, and even responsible for controversies in this field. In a closing section, controversial. Space limitations make it impossible to cover we will summarize important aspects of these phenomena that the entire field, or to do justice to the many important have not yet received much experimental analysis. The contributions made by different laboratories over the years. information summarized in this article has been derived from studies on embryos from several different experimental animal species, including amphibians, chick, mouse, and to a lesser extent rat and fish. Although inter-specific differences are only ⁎ Corresponding author. Department of Ophthalmology, Johns Hopkins School of Medicine, 600 N. Wolfe Street, 519 Maumenee, Baltimore, MD considered in some detail in Section V-B, it is not unlikely that 21287-9257, USA. Fax: +1 410 955 0749. they could also be relevant to phenomena described in other E-mail address: [email protected] (R. Adler). parts of the article.

Structural aspects of optic vesicle development Inductive interactions during OV development

The initial indication of optic vesicle (OV) formation is the An extensive series of inductive tissue interactions must appearance of symmetrical bilateral evaginations from the occur for the OV to appear, develop, and integrate with diencephalon, which slowly expand through the mesenchyme neighboring tissues. They actually begin well before the first towards the surface ectoderm (Fig. 1A). As contact between morphological indications of OV development, as illustrated by the OV and the ectoderm is established (Fig. 1B), both tissues the induction and regionalization of the neural plate by the undergo complex (and temporally correlated) structural “organizer” (Kessler and Melton, 1994; Streit and Stern, 1999), changes. The ectoderm thickens initially into a “lens placode” and the induction of an “eye field” within the anterior neural (Fig. 1B), which invaginates into a vesicle that eventually plate (Esteve and Bovolenta, 2006; Moore et al., 2004; Zuber et closes and separates completely from the surface ectoderm al., 2003). The eye field is located in the anterior neural plate, (Figs. 1C–D). The concomitant invagination of the OV is more surrounded by telencephalic precursors and by cells that will complex, resulting in the formation of an optic cup (OC) that form the hypothalamus (Esteve and Bovolenta, 2006). The has a double wall, and is connected to the diencephalon by precordal mesoderm plays a key role in determining the eye the optic stalk (Figs. 1C–E). The invagination of the dorsal field and its subdivision into two separate domains, the future aspect of the optic vesicle (Fig. 1C) generates an internal layer bilateral optic vesicles (Li et al., 1997). As the evaginating optic (the neural retina) and an external layer, the retinal pigment vesicles make contact with the mesenchyme and the ectoderm, epithelium (RPE), whereas more ventrally the OV narrows they form a highly interactive system in which numerous considerably into the “choroid fissure” (Figs. 1C′, D). The consecutive, and frequently reciprocal inductive interactions fissure closes completely in normal development, forming the take place. The specification of the neural retina and RPE optic nerve through which retinal ganglion cell axons grow domains within the OV appears to be determined by inductive towards the brain (Fig. 1E); its abnormal persistence is known signals originating in the surface ectoderm and in the as “coloboma”. mesenchyme, respectively (Fuhrmann et al., 2000; Vogel-

Fig. 1. Schematic representation of vertebrate eye development. (A) The optic vesicle forms as an evagination from the diencephalon. (B) Upon contact with the surface ectoderm, the optic vesicle becomes patterned into presumptive RPE, neural retina and optic stalk; the surface ectoderm in turn forms the lens placode. (C) The optic vesicle and lens placode invaginate, giving rise to the optic cup and the lens vesicle, respectively. (C′) The ventral region of the invaginating optic vesicle forms the choroid fissure. (D–E) Transition from early to mature optic cup. The lens vesicle loses its cavity and becomes a solid structure; the neural retina and the pigment epithelium become apposed, reducing ependymal cavity to a virtual space; the optic stalk gives riseto the optic nerve, and the surface ectoderm adjacent to the lens gives rise to the corneal epithelium. Abbreviations: C: Cornea; L: lens; LP: lens placode; LV: lens vesicle; MS: mesenchyme; NR: neural retina; ON: optic nerve; OS: optic stalk; OV: optic vesicle; RPE: retinal pigment epithelium; S: sclera; SE: surface ectoderm. R. Adler, M.V. Canto-Soler / Developmental Biology 305 (2007) 1–13 3

Hopker et al., 2000; Zhao et al., 2001). In turn, inductive portant role in regulating Wnt and FGF signaling during the influences from the optic vesicle derivatives influence further early events leading to optic vesicle formation (Filipe et al., development of the lens (Chow and Lang, 2001; Grainger et al., 2006; Yamamoto et al., 2005). One of the factors involved in 1997; Lovicu and McAvoy, 2005). The dorso-ventral patterning splitting the eye field is a secreted Nodal-related member of the of the optic cup is regulated by a balance between opposing TGF-β superfamily encoded by the Cyclops (Cyc) gene (Muller signals originating in the neural tube and/or the optic stalk on et al., 2000; Varga et al., 1999), perhaps acting through the one hand, and in the dorsal region of the optic cup on the other. induction of SHH expression (Chow and Lang, 2001; Ekker The lens also influences the formation of the iris and ciliary et al., 1995; Li et al., 1997; Macdonald et al., 1995; Marti and body, specialized structures at the peripheral margin of the optic Bovolenta, 2002; Muller et al., 2000; Pera and Kessel, 1997; cup (Hyer, 2004). Several aspects of these interactions will be Wilson and Houart, 2004). SHH, in turn, contributes to the discussed in more detail below. normal separation of the eye field into two optic vesicles by regulating its proximo-distal patterning (Chow and Lang, 2001; Extracellular signaling molecules and transcription factors Ekker et al., 1995; Macdonald et al., 1995; Take-uchi et al., involved in OV induction and development 2003; Wilson and Houart, 2004). As already mentioned, patterning of the OV neuroepithelium Extracellular signaling molecules into neural retina (NR) and retinal pigment epithelium (RPE) depends on inductive signals from neighboring surface ectoderm The secreted signaling molecules involved in the regulation and mesenchyme. FGF family members expressed in the surface of eye development belong to a “surprisingly restricted number ectoderm appear to induce neural retina formation (reviewed of gene families” (Esteve and Bovolenta, 2006), including by Bharti et al., 2006; Chow and Lang, 2001; Martinez-Morales hedgehog (Hh), Wnt, transforming growth factor β (TGF-β), et al., 2004). In addition, upon contact with the surface ectoderm bone morphogenetic proteins (BMPs), and fibroblast growth the prospective neural retina itself expresses FGF8 and FGF9, factor (FGF). Many of these signaling molecules reappear at both of which play a role in defining the boundary between NR different stages of eye development, controlling different and RPE (Galy et al., 2002; Horsford et al., 2005; Vogel-Hopker developmental events, as summarized in Table 1. FGF and the et al., 2000; Zhao et al., 2001; among others). Extraocular Wnt non-canonical pathway have been shown to regulate the mesenchyme promotes RPE differentiation, on the other hand, morphogenetic movements of progenitor cells towards the eye possibly through an activin-like signal (Fuhrmann et al., 2000; field in Xenopus (Lee et al., 2006; Moody, 2004; Moore et al., Kagiyama et al., 2005; reviewed by Bharti et al., 2006; Chow 2004). The non-canonical branch of the Wnt signaling pathway and Lang, 2001; Martinez-Morales et al., 2004). BMP7 subsequently ensures the cohesion of progenitor cells in the eye expression within the prospective RPE domain helps to maintain field (Cavodeassi et al., 2005), while its canonical/βcatenin the identity of this tissue by antagonizing possible neuralizing branch has to be dowregulated or inhibited for the eye field to effects of FGF (Vogel-Hopker et al., 2000). SHH is also required differentiate from the diencephalic region (reviewed by Esteve for the dorso-ventral and central-to-periphery patterning of the and Bovolenta, 2006; Wilson and Houart, 2004). In addition, optic cup at a later stage (Zhang and Yang, 2001; reviewed by interplay between the non-canonical Wnt pathway and BMP Peters, 2002). BMPs and retinoic acid (RAc) have also been appears to influence the establishment of a boundary between considered important players in dorso-ventral patterning telencephalon and eye field (reviewed by Esteve and Bovolenta, regulation; their specific roles remain controversial, however, 2006). Shisa, a recently identified protein, may play an im- and will be discussed below.

Table 1 Extracellular molecules involved in eye development through early optic cup stages Events during eye development Extracellular molecules References Specification of the eye field FGFs; Wnts; BMPs Cavodeassi et al., 2005; Esteve and Bovolenta, 2006; Lee et al., 2006; Moody, 2004; Moore et al., 2004; Wilson and Houart, 2004 Splitting of the eye field and Cyclops; SHH Chow and Lang, 2001; Ekker et al., 1995; Li et al., 1997; Macdonald et al., 1995; proximo-distal patterning Marti and Bovolenta, 2002; Muller et al., 2000; Pera and Kessel, 1997; of the OV Take-uchi et al., 2003; Varga et al., 1999; Wilson and Houart, 2004 Patterning of the OV SHH; FGFs; Activin; BMP7; Bharti et al., 2006; Chow and Lang, 2001; Fuhrmann et al., 2000; Galy et al., 2002; RA Horsford et al., 2005; Kagiyama et al., 2005; Martinez-Morales et al., 2004; Vogel-Hopker et al., 2000; Zhao et al., 2001 Invagination of the optic vesicle RA Hyer et al., 2003; Matt et al., 2005; Mic et al., 2004; Molotkov et al., 2006 into an optic cup Antero-posterior and Dorso-Ventral Nodal; FGFs; SHH; BMPs; RA; Adler and Belecky-Adams, 2002; Belecky-Adams and Adler, 2001; patterning of the optic cup Ventroptin; Follistatin, Chordin, Huillard et al., 2005; Koshiba-Takeuchi et al., 2000; Morcillo et al., 2006; Peters, 2002; Noggin; DAN Sakuta et al., 2001; Sakuta et al., 2006; Yang, 2004; Zhang and Yang, 2001 BMPs: bone morphogenetic proteins; DAN: DAN domain family members; FGFs: fibroblast growth factors; RA: retinoic acid; SHH: sonic hedgehog; Wnts: members of the Wnt family. 4 R. Adler, M.V. Canto-Soler / Developmental Biology 305 (2007) 1–13

Transcription factors retina, and Pax6, Otx2 and Mitf in the prospective RPE (Bharti et al., 2006; Chow and Lang, 2001; Martinez-Morales et al., Transcription factors are also frequently involved in the 2004). Reciprocal transcriptional repression between transcrip- regulation of more than one aspect of eye development, as tion factors may contribute to establishing boundaries between summarized in Table 2 (Bailey et al., 2004; Chow and Lang, developing territories (e.g., Pax6 and Pax2 for neural retina and 2001; Esteve and Bovolenta, 2006). Rx, Pax6 and Otx2 have optic stalk, Chx10 and Mitf for neural retina and RPE (Canto- been shown to play a role in the morphogenetic movements Soler and Adler, 2006; Horsford et al., 2005; Schwarz et al., leading to eye field formation, probably under the influence of 2000). extra-cellular signaling molecules (Esteve and Bovolenta, Pax6, Hes1, and Lhx2 are necessary for proper growth of the 2006). In addition, the coordinated expression of Rx, Pax6, optic vesicle and its transformation into an optic cup. As Six3, Lhx2, Six6/Optx2, ET and tll appears essential for the discussed below in some detail, Pax6 downregulation in the specification of the eye field (Bailey et al., 2004; Chow and optic vesicle neuroepithelium affects the survival of optic Lang, 2001; Viczian et al., 2006; Wilson and Houart, 2004; vesicle cells and the transformation of the OV into a normal Zuber et al., 2003). Although knockout and mis-expression optic cup (Canto-Soler and Adler, 2006). Similarly, Lhx2 experiments have shown that some of these genes can regulate knockout mice develop optic vesicles, but optic cup and lens each other's expression, their epistatic relationships are not clear formation fail to occur (Porter et al., 1997; reviewed by Chow (Chow and Lang, 2001; Zuber et al., 2003). Interestingly, early and Lang, 2001). The phenotype of Hes1 mutant mice varies eye development also appears to be influenced by transcription from a reduced lens accompanied by a smaller than normal optic factors that are not expressed in the eye field, such as Hes1 and cup, to the complete absence of the lens with an arrested optic Otx2, which may act indirectly by regulating forebrain vesicle (Lee et al., 2005; Tomita et al., 1996). development (Bailey et al., 2004; Chow and Lang, 2001). In the optic cup, interactions between Pax6, Pax2, cVax and Several transcription factors have also been shown to Tbx5 mediate dorso-ventral patterning of the neural retina influence optic vesicle formation and/or evagination, which (Canto-Soler and Adler, 2006; Leconte et al., 2004; reviewed by fail to occur in Rx mouse mutants and are abnormal in Pax6 Chow and Lang, 2001; Peters, 2002). In addition, Pax6 activity mouse mutants through still unknown mechanisms (Bailey et is required for the establishment and maintenance of dorsal and al., 2004; Chow and Lang, 2001). Analysis of Rx3 mutants in naso-temporal characteristics (Baumer et al., 2002). Other medaka and zebrafish suggested that it may affect optic vesicle transcription factors also involved in naso-temporal patterning evagination by influencing active cell migration from the eye of the neural retina are BF-1/Foxg1, BF-2/Foxd2, SOHo1 and field (Loosli et al., 2003, 2001; Rembold et al., 2006). In GH6 (Takahashi et al., 2003; Yuasa et al., 1996; reviewed by addition, inhibition of tll has also been shown to interfere with Chow and Lang, 2001; Peters, 2002). optic vesicle evagination in Xenopus (Hollemann et al., 1998). Neuroepithelial cells of the early optic vesicle co-express Rx, Complexities, ambiguities and controversies in OV Pax6, Hes1, Otx2, Lhx2, Six3 and Six9 while they are still research competent to originate optic stalk, neural retina and RPE (reviewed by Chow and Lang, 2001; Martinez-Morales et al., Lens induction, one of the first developmental phenomena to 2004). The subsequent specification of these OV derivatives is be studied experimentally, has provided fertile ground for accompanied by differential expression of these and other controversial and even contradictory conclusions, particularly transcription factors: Pax2 and Vax in the prospective optic regarding whether the optic vesicle is essential for lens stalk; Pax6, Rx, Lhx2 and Chx10 in the prospective neural development to start and/or proceed (Lovicu and McAvoy,

Table 2 Transcription factors involved in eye development through early optic cup stages Events during eye development Transcription factors References Specification of the Rx; Pax6; Six3; Lhx2; Bailey et al., 2004; Bovolenta, 2006; Chow and Lang, 2001; Esteve and Zuber, 2003; eye field Six6/Optx2; ET; tll; Hes1; Otx2 Viczian et al., 2006; Wilson and Houart, 2004 Optic vesicle evagination Rx; Pax6; tll Bailey et al., 2004; Chow and Lang, 2001; Hollemann et al., 1998; Loosli et al., 2001; Loosli et al., 2003; Rembold et al., 2006 Optic vesicle dorso-ventral Pax6; Rx; Lhx2; Chx10; Otx2; Bharti et al., 2006; Canto-Soler and Adler, 2006; Chow and Lang, 2001; Horsford et al., 2005; patterning Mitf; Pax2; Vax Martinez-Morales et al., 2004; Schwarz et al., 2000 Optic vesicle naso-temporal BF1/Foxg1; BF2/Foxd2; Pax6 Baumer et al., 2002; Hatini et al., 1994; Yuasa et al., 1996 patterning Optic vesicle invagination Pax6; Lhx2; Hes1 Canto-Soler and Adler, 2006; Chow and Lang, 2001; Lee et al., 2005; Porter et al., 1997; into an optic cup Tomita et al., 1996 Neural retina dorso-ventral Pax6, Pax2, Vax, Tbx5; Xbr1 Canto-Soler and Adler, 2006; Chow and Lang, 2001; Leconte et al., 2004; Mui et al., 2005; patterning Peters, 2002 Neural retina naso-temporal Pax6; BF1/Foxg1; BF2/Foxd2; Baumer et al., 2002; Chow and Lang, 2001; Peters, 2002; Takahashi et al., 2003; patterning SOHo1; GH6 Yuasa et al., 1996 R. Adler, M.V. Canto-Soler / Developmental Biology 305 (2007) 1–13 5

2005; Sullivan et al., 2004). The diverging results obtained by the ventro-dorsal patterning of the spinal cord (reviewed by different investigators were eventually ascribed to differences in Jessell, 2000), ventral Shh signals and dorsal BMP4 signals act methodology, in the selection of experimental animals, and/or in antagonistically, establishing and maintaining distinct ventral the developmental stages and end points used to analyze these and dorsal eye compartments respectively (Peters, 2002; Yang, complex phenomena. Perhaps not surprisingly, equivalent 2004; Zhang and Yang, 2001). Against this background, it was discrepancies and controversies have emerged more recently surprising to find that inhibition of BMP signaling by noggin among experimental studies of other aspects of early eye over-expression caused extensive abnormalities of ventral eye development that, like lens induction, are complex multi-step structures, whose severity varied considerably as a function of processes, rather than simple one-step phenomena. These the stage of the embryo at treatment onset (Adler and Belecky- complications are the rule rather than the exception, and should Adams, 2002). Noggin overexpression at optic vesicle stages in fact be expected and anticipated by researchers in this field. resulted in microphthalmia with concomitant disruption of the We will illustrate the point by describing, in the context of the developing neural retina, RPE and lens, whereas the same appropriate literature, the complexities that we encountered in treatment started at optic cup stages did not affect the size and designing and interpreting two recent studies of micro- general organization of the eye, but caused colobomas, absence environmental factors and transcriptional regulators involved of the pecten, transdifferentiation of the ventral RPE into in optic cup development (Adler and Belecky-Adams, 2002; neuroepithelium-like tissue, ectopic expression of optic stalk Canto-Soler and Adler, 2006). markers in the ventral retina and RPE, and ectopic growth of optic nerve fibers towards the lens (Adler and Belecky-Adams, The complexity of extra-cellular signaling systems in optic cup 2002). Similar results were obtained with a dominant negative development BMP receptor (Adler and Belecky-Adams, 2002), by overexpression of DRM-gremlin, another BMP inhibitor (Huillard The dorsal and ventral regions of the optic cup show et al., 2005), an in BMP7-deficient mice (Morcillo et al., 2006). many differences since early embryonic stages. They include: i) These results imply that endogenous BMPs regulate ventral structural differences (e.g., the dorsal retina expands faster than optic cup development despite their co-existence with a variety the ventral retina, and the latter forms a choroid fissure of BMP inhibitors, including follistatin, follistatin-like protein (Koshiba-Takeuchi et al., 2000); ii) molecular differences (flik), DAN, chordin, noggin and ventroptin (Belecky-Adams (e.g., they express different transcription factors (Barbieri et and Adler, 2001; Belecky-Adams et al., 1999; Eimon and al., 1999; Koshiba-Takeuchi et al., 2000; Macdonald et al., Harland, 2001; Ogita et al., 2001; Sakuta et al., 2001). The data 1995; Ohsaki et al., 1999; Schulte et al., 1999; Torres et al., also suggest that BMP agonists and antagonists must exist in a 1996), retinoic acid synthesizing enzymes (McCaffery et al., precisely fine-tuned equilibrium within optic cup tissues. It must 1999; Mey et al., 2001; Suzuki et al., 2000), ephrins and ephrin be noted also that the developing optic cup and adjacent tissues receptors (Braisted et al., 1997; Holash and Pasquale, 1995; express several BMPs in addition to BMP4 (Belecky-Adams Holash et al., 1997; Marcus et al., 1996) and BMPs (Belecky- and Adler, 2001); BMP7 is expressed near the optic stalk and in Adams and Adler, 2001); and iii) functional differences (e.g., the ventral pigment epithelium, for example, and is therefore they project to different brain regions (Braisted et al., 1997; strategically located to influence the ventral retina (Belecky- Thanos and Mey, 2001), and respond differently to various Adams and Adler, 2001; Vogel-Hopker et al., 2000). BMP regulatory molecules (Hyatt and Dowling, 1997; Marsh- receptors IA and IB, moreover, are predominantly if not Armstrong et al., 1994; Zhang and Yang, 2001). There has exclusively localized to the ventral retina and optic stalk at early been considerable interest, therefore, on the signals that developmental stages (Belecky-Adams and Adler, 2001). Taken influence the dorso-ventral patterning of the retina. together, these findings disclose three layers of complexity that Retinoic acid and sonic hedgehog have been generally are shared by other signaling systems in the developing optic recognized as regulators of ventral retinal development (Hyatt cup, and are illustrated in Fig. 2. They are: i) families of growth et al., 1996a,b; Kastner et al., 1994; Marsh-Armstrong et al., factors are frequently represented by many members in the optic 1994; Zhang and Yang, 2001), whereas the BMPs (and cup and adjacent tissues, ii) they frequently coexist with particularly BMP4) have been described predominantly as inhibitors, and iii) tissues that are morphologically homo- regulators of dorsal retinal development (Koshiba-Takeuchi et geneous show heterogeneity in the distribution of signaling al., 2000; Zhang and Yang, 2001; reviewed by Peters, 2002). molecules and their inhibitors and receptors. Representative Their roles, however, are currently under revision. BMP4 is examples of other families of growth factors showing similar restricted to the dorsal region of the optic cup, and its complexities are FGFs and their respective high and low affinity experimental over-expression has dorsalizing effects upon the receptors (Fig. 2B) (Francisco-Morcillo et al., 2005; Hicks, ventral retina (Koshiba-Takeuchi et al., 2000; Sasagawa et al., 1998; Itoh and Ornitz, 2004; Kurose et al., 2005; Lovicu and 2002; Trousse et al., 2001). During normal development, the McAvoy, 2005; Ornitz and Itoh, 2001; Vogel-Hopker et al., ventral retina is apparently protected from these effects by 2000; Yamashita et al., 2000) and the Wnts (Fig. 2C) (Fokina ventroptin, a BMP inhibitor (Koshiba-Takeuchi et al., 2000; and Frolova, 2006; Fuhrmann et al., 2003; Jin et al., 2002; Liu Sakuta et al., 2001), and by sonic hedgehog (SHH), a et al., 2003; Van Raay and Vetter, 2004). ventralizing agent (Zhang and Yang, 2001). These results led An additional complication for the interpretation of noggin to the formulation of a model proposing that, as in the case of overexpression experiments was that at least some of its effects 6 R. Adler, M.V. Canto-Soler / Developmental Biology 305 (2007) 1–13

Fig. 2. Schematic representation of the distribution of members of several families of extracellular signaling systems in the developing optic cup. The data shown corresponds predominantly to in situ hybridization results. Gradients of color represent the superposition of expression domains of different molecules, rather than gradients of expression of individual molecules (for the sake of clarity, only the region corresponding to the highest level of expression has been represented for those molecules whose pattern of expression follows high-to-low gradients). (A) BMPs, its receptors, antagonists and inhibitors (modified and up-dated from Belecky- Adams, unpublished). (B) Wnts, its receptors and antagonists (modified and up-dated from Van Raay and Vetter, 2004). (C) FGFs, its receptors and antagonists. Abbreviations: BMP: bone morphogenetic proteins; CRF: cysteine-rich FGF receptors; Dan: members of the Dan protein family; FGF: fibroblast growth factors; Fz: frizzled receptors; Sfrp: secreted frizzled related proteins; Spry: sprouty protein; Wnt: members of the Wnt family. on ventral retina could be indirect, resulting from primary normally attracts ganglion cell axons into the optic nerve (de la effects on other tissues and/or by changes in the expression of Torre et al., 1997; Deiner et al., 1997; Livesey and Hunt, 1997; other signaling molecules. Such indirect effects would not be Petrausch et al., 2000; Sugimoto et al., 2001). Similarly, the without precedent. For example, lens induction was absent in apparent transdifferentiation of ventral eye tissues induced by BMP4 homozygous null mutant embryos, and could be rescued noggin over-expression was accompanied by the upregulation by exogenous BMP4 protein (Furuta and Hogan, 1998), of FGF-8 (Adler and Belecky-Adams, 2002) which can induce suggesting that BMP4 has a direct effect on lens induction. RPE transdifferentiation (Vogel-Hopker et al., 2000); it is However, the same authors found that BMP4 failed to induce noteworthy that these authors suggested that BMP7, produced lens when it was applied to ectoderm in the absence of optic by the pigment epithelium, prevents FGF8 from inducing RPE vesicle, leading to the conclusion that BMP4 is in fact required transdifferentiation during normal eye development. Noggin- within the optic vesicle itself to determine its lens-inducing treated retinas also showed upregulation of ALDH6, a retinoic activity. Our finding that noggin over-expression in the retina acid-synthesizing enzyme, suggesting that retinoic acid may induced alterations in lens development (Belecky-Adams et al., also have contributed to the observed changes in the ventral 2002) raised the possibility that such lens alterations could retina. The notion that endogenous retinoic acid plays a critical affect its capacity to interact with the retina, particularly role in dorso-ventral retinal patterning is supported by i) considering the complexity of the effects of BMP4 and BMP7 localization studies in several species (Drager et al., 2001; on lens induction (Dudley et al., 1995; Jena et al., 1997; Duester et al., 2003; Luo et al., 2006; Matt et al., 2005; Peters Karsenty et al., 1996; Luo et al., 1995; Solursh et al., 1996; and Cepko, 2002; Wagner et al., 2000), ii) experiments showing Wawersik et al., 1999). Noggin-induced mis-direction of that treatment of the zebrafish eye with retinoic acid leads to ganglion cell axons away from the optic stalk also appeared duplication of the ventral retina (Hyatt et al., 1992), and iii) the to be indirect, since it was accompanied by an intraretinal finding that the inhibition of RAc synthesis with citral has the expansion of the domain of expression of netrin (Adler and opposite effects (Marsh-Armstrong et al., 1994). On the other Belecky-Adams, 2002), an axonal guidance molecule that hand, loss-of-function experiments in the chick have suggested R. Adler, M.V. Canto-Soler / Developmental Biology 305 (2007) 1–13 7 that RAc indeed plays a role in regulating the expression of (Canto-Soler and Adler, 2006; Reza and Yasuda, 2004), while dorso-ventral topographic guidance molecules in the retina, but supportive evidence for the Pax6/lens model derived from does so without altering the expression of transcription factors mouse and rat studies (Ashery-Padan et al., 2000; Davis- involved in dorso-ventral patterning, such as Tbx5 or Vax (Sen Silberman et al., 2005; Fujiwara et al., 1994; Hill et al., 1991; et al., 2005). Equivalent results have been recently reported in Hogan et al., 1988; Zhang et al., 2000). Such possible inter- the mouse (Matt et al., 2005; Molotkov et al., 2006). Obviously, specific differences are unlikely to be the only explanation, indirect effects of signaling molecules are far from exceptional however, because it has been reported that, prior to the time of in a highly integrated and interactive system like the developing lens placode formation, Sey/Sey mouse OVs already are eye. abnormally broad, and fail to constrict proximally (Grindley et al., 1995); analysis of Pax6 chimeric mice, moreover, The complexity of transcription factor effects: role of Pax6 in suggested that Pax6 is required in the OV for maintenance of optic cup development contact with the overlying lens epithelium (Collinson et al., 2000). The very dynamic nature of the optic vesicle and Heterozygous mutations in the Pax6 homeobox gene cause surrounding tissues is another likely contributor to differences human aniridia and Peter's anomaly (Glaser et al., 1992; in experimental outcomes between studies, or even within one Hanson et al., 1994; Jordan et al., 1992), and the small eye same study. In our experiments, for example, Pax6 down- phenotype in mice and rats (Hill et al., 1991; Matsuo et al., regulation was already detectable in the OV 10 h after anti-Pax6 1993). Anophthalmia can result either from loss-of-function morpholino electroporation, and was accompanied by a Pax6 mutations (Glaser et al., 1994; Hill et al., 1991) or from significant increase in the death of OV cells; the magnitude Pax6 overexpression, suggesting dosage-dependent effects and phenotypic consequences of these changes, however, were (Schedl et al., 1996). The elucidation of the underlying dramatically different depending on the embryonic stage at mechanisms has been challenging due to the reciprocal treatment onset (Canto-Soler and Adler, 2006). When morpho- inductive interactions between the OV and the lens ectoderm, linos were electroporated at Hamburger Hamilton (HH) stage and to the complex patterns of Pax6 expression in both 10, there was no optic cup formation, and lens development was structures (Belecky-Adams et al., 1997; Grindley et al., 1995; Li abortive despite normal Pax6 expression in the lens epithelium. et al., 1994; Walther and Gruss, 1991; reviewed by Chow and On the other hand, treatment at HH stage 11 resulted in Lang, 2001). Until recently, there was general (but not structurally normal lens and optic cup, although the latter universal) acceptance of the notions that i) Pax6 is not essential showed abnormal expression domains for several transcription for optic vesicle formation or for the establishment of the NR factors. What makes these differences even more striking is that and RPE domains; ii) the primary defect leading to the small the time interval between stages 10 and 11 is only 7 h. An eye phenotype is the failure of the surface ectoderm to form a important corollary of these findings is that, if we had done our lens placode, which in turn leads to degeneration of the OV; and experiments only at HH stage 11, they would have yielded iii) lens development requires Pax6 activity in the prospective results consistent with the Pax6/lens model, rather than with the lens ectoderm but not in the optic vesicle (reviewed by Ashery- Pax6/lens-OV model. Crucial for the outcome of our experi- Padan and Gruss, 2001; Lang, 2004; Mathers and Jamrich, ments was the high temporal resolution offered by the 2000; Ogino and Yasuda, 2000) This view will be referred combination of electroporation techniques and morpholino henceforth as the “Pax6/lens” model. Surprisingly, experiments oligonucleotides, whose antisense activity starts very shortly in which anti-Pax6 morpholinos were electroporated into the after treatment. The timing of this experimental treatment may chick embryo optic vesicle before the onset of lens placode be different from that of other approaches, such as cre-lox formation (Canto-Soler and Adler, 2006) showed that i) early dependent Pax6 inactivation (Ashery-Padan et al., 2000; Davis- eye development requires cell-autonomous Pax6 function not Silberman et al., 2005) or expression of dominant negative only in the lens but also in the optic vesicle; ii) a small-eye like constructs (Reza and Yasuda, 2004). phenotype can occur even when Pax6 is normally expressed in Some of the discrepancies between the Pax6/lens-OV and the surface ectoderm; iii) Pax6 expression in the OV is Pax6/lens models may only be apparent, and may result from necessary for the survival of retinal progenitor cells and for the “end points” used to evaluate experimental outcomes. The the specification of NR and RPE domains; iv) Pax6 expression notion that Pax6 expression in the lens epithelium is necessary in the optic vesicle is also necessary for normal lens for normal lens development has been well supported by development during a critical developmental stage; and v) experiments using conditional knockouts and chimeras in the Pax6 expression in the lens is necessary, but not sufficient for mouse (Ashery-Padan et al., 2000; Collinson et al., 2000; Quinn normal less development. We will refer to this view as the et al., 1996). On the other hand, the notion that Pax6 expression “Pax6/lens-OV” model. Although these discrepancies have not inthelensisalsosufficient for lens development is yet been fully resolved, they provide useful insights into the predominantly based on recombination experiments using factors that complicate experimental analysis of early eye tissues isolated from wild type and small eye (rSey/rSey) rats development. (Fujiwara et al., 1994). These experiments showed that the onset Possible differences between chick and mouse/rat embryos of lens formation depends upon the genotype of the surface could contribute to the discrepancies, since the Pax6/lens-OV ectoderm, and is independent of the genotype of the optic model was supported by experiments with chick embryos vesicle. However, the recombination experiments were not long 8 R. Adler, M.V. Canto-Soler / Developmental Biology 305 (2007) 1–13 enough to allow evaluating the degree of differentiation reached in the optic cup, beyond the demonstration that optic cup by the lens in each case, and it is therefore unknown whether formation involves changes in cell shape accompanied by lens development would have become arrested in the presence apparent increases in the number of microtubules (during cell of Sey/Sey optic vesicles, as it did in the chick studies when elongation) and microfilaments (during apical cell constriction) Pax6 was downregulated in the optic vesicle (Canto-Soler and (Brady and Hilfer, 1982; Schook, 1980; Svoboda and O'Shea, Adler, 2006; Reza and Yasuda, 2004). This possibility is not 1984, 1987). This is particularly surprising in view of the unlikely given that lens development appears to occur through frequency with which optic cup morphogenesis results in at least 4 distinct stages, which may be regulated by different abnormal defects of choroid fissure closure known as coloboma mechanisms (Grainger et al., 1992; Grainger et al., 1988; (Gregory-Evans et al., 2004; Onwochei et al., 2000), which can Grainger et al., 1997; Henry and Grainger, 1987; Saha et al., be caused by genetic factors such as mutations/deletions in Pax2 1989). The dynamic nature of the lens epithelium may also (reviewed by Dressler and Woolf, 1999), Vax (Hallonet et al., explain controversies regarding whether the lens is needed for 1999), Pitx2 (Gage et al., 1999), and Sox10 (Bondurand et al., the invagination of the optic vesicle and the formation of the 1999), and/or from changes in extracellular signaling molecules neural retina. Thus, cre-lox inactivation of Pax6 in the lens led including SHH overexpression (Zhang and Yang, 2001), and to the conclusion that the lens itself is not needed for optic cup decreases in the availability of retinoic acid (Stull and Wikler, invagination or the appearance of a retina (although it is for its 2000) or the BMPs (Adler and Belecky-Adams, 2002). It placement; Ashery-Padan et al., 2000) whereas more recent appears that the morphogenesis of the optic cup provides fertile experiments confirmed that the lens itself is not necessary, but ground for new investigations. showed that the optic vesicle neuroepithelium does require a temporally specific association with pre-lens ectoderm in order Epigenetic controls to undergo morphogenesis into an optic cup (Hyer et al., 2003; Khosrowshahian et al., 2005). Epigenetic mechanisms of gene expression control, including RNA-associated silencing, DNA methylation and histone Aspects of OV development that have not received modification, are being increasingly recognized as playing key extensive attention roles in the control of normal embryonic development in a variety of tissues and species (reviewed by Bartel, 2004; While no aspect of optic vesicle formation and development Finnegan and Matzke, 2003; Grewal and Rice, 2004; Klooster- has been fully explained, progress has been quite substantial in man and Plasterk, 2006; Lapidot, 2006; Song and Tuan, 2006; many areas, and the existing momentum in their investigation is Werner, 2005). Examples in the nervous system include control reason for optimism that progress will continue at a fast pace. of the timing of cell differentiation, the neuron versus glia fate On the other hand, there are several aspects of optic vesicle choice of progenitor cells, neuronal plasticity, and dendritic development that, despite their importance, have received spine development, among others (Abrahante et al., 2003; relatively little attention. Without attempting to be comprehen- Conaco et al., 2006; Lin et al., 2003; Schratt et al., 2006; Vo sive, we will close this article with an overview of two such et al., 2005; reviewed by Hsieh and Gage, 2004; Hsieh and areas. Gage, 2005; Song and Tuan, 2006). In contrast, there is only a very limited body of literature dealing with these mechanisms in Morphogenetic mechanisms the developing eye. The timing of bHLH transcription factor function during retinal cell differentiation can be regulated post- The invagination of the optic cup and the lens vesicle offers a translationally, and there seems to be a correlation between striking example of precisely coordinated (and complex) chromatin modifications and binding of these transcription morphogenetic phenomena. The regulation of both phenomena factors (Moore et al., 2002; Skowronska-Krawczyk et al., 2004). by micro-environmental factors has been studied. Many aspects More recently, several miRNAs, as well as natural antisense of lens morphogenesis are profoundly influenced by micro- transcripts (NATs) for transcription factors such as Pax6, Pax2, environmental factors, as shown by a series of elegant lens Six3, Six6, Otx2, Crx, Rax and Vax, have been identified in vesicle transplantation experiments in the chick embryo vertebrate ocular tissue and found to exhibit distinct patterns of (Coulombre and Coulombre, 1963; reviewed by Lovicu and tissue and cell type distribution (Alfano et al., 2005; Frederikse McAvoy, 2005). More recent experiments from several et al., 2006; Ryan et al., 2006). In Drosophila, moreover, laboratories have shown that micro-environmental influences miRNA7 has been shown to promote photoreceptor differentia- can also determine whether optic cup formation does or does tion (Li and Carthew, 2005). Despite these important but isolated not occur; they include the pre-lens ectoderm (Hyer et al., findings, there is not yet a clear understanding of the role of 2003), and retinoic acid (Matt et al., 2005; Mic et al., 2004; epigenetic mechanisms in eye development. The paucity of Molotkov et al., 2006). Considerable efforts have also been information is even more conspicuous in the case of OV devoted to the analysis of the mechanisms of lens invagination, development; to the best of our knowledge, only two publica- including possible complex changes in cell adhesion, cell shape, tions directly address these mechanisms. One of them is a cell proliferation, cell death, and/or extracellular matrix description of the expression and function of Xenopus BMD3, a molecules (reviewed by Menko et al., 1998; Zelenka, 2004). protein that specifically binds to methylated DNA, is highly There has been much less work devoted to similar phenomena expressed in the prospective eye region, and can influence early R. Adler, M.V. Canto-Soler / Developmental Biology 305 (2007) 1–13 9 aspects of eye development (Iwano et al., 2004). In the other, the developing chick retina: expression patterns, protein distribution, and in – the capacity of the Vax2 protein to repress Pax6 expression vitro effects. Dev. Biol. 210, 107 123. Belecky-Adams, T.L., Adler, R., Beebe, D.C., 2002. Bone morphogenetic during the differentiation of the OV neuroepithelium was protein signaling and the initiation of lens fiber cell differentiation. shown to be regulated by its phosphorilation/dephosphorila- Development 129, 3795–3802. tion, which in turn controls its translocation from the Bharti, K., Nguyen, M.T., Skuntz, S., Bertuzzi, S., Arnheiter, H., 2006. The cytoplasm to the nucleus (Kim and Lemke, 2006). Considering other pigment cell: specification and development of the pigmented – the current pace of progress in understanding the significance epithelium of the vertebrate eye. Pigm. Cell Res. 19, 380 394. Bondurand, N., Kuhlbrodt, K., Pingault, V., Enderich, J., Sajus, M., Tommerup, of epigenetic mechanisms in normal development in general, it N., Warburg, M., Hennekam, R.C., Read, A.P., Wegner, M., Goossens, M., is to be expected that the investigation of their role in optic 1999. 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