Early development of the cranial sensory nervous system: from a common field to individual placodes

Developmental Biology 276 (2004) 1 – 15 www.elsevier.com/locate/ydbio

Review

Early development of the cranial sensory nervous system: from a common field to individual placodes Andrea Streit Department of Craniofacial Development, King’s College London, Guy’s Campus, London SE1 9RT, UK Received for publication 23 April 2004, revised 20 August 2004, accepted 23 August 2004 Available online 30 September 2004

Abstract Sensory placodes are unique columnar epithelia with neurogenic potential that develop in the vertebrate head ectoderm next to the neural tube. They contribute to the paired sensory organs and the cranial sensory ganglia generating a wide variety of cell types ranging from lens fibres to sensory receptor cells and neurons. Although progress has been made in recent years to identify the molecular players that mediate placode specification, induction and patterning, the processes that initiate placode development are not well understood. One hypothesis suggests that all placode precursors arise from a common territory, the pre-placodal region, which is then subdivided to generate placodes of specific character. This model implies that their induction begins through molecular and cellular mechanisms common to all placodes. Embryological and molecular evidence suggests that placode induction is a multi-step process and that the molecular networks establishing the pre-placodal domain as well as the acquisition of placodal identity are surprisingly similar to those used in Drosophila to specify sensory structures. D 2004 Elsevier Inc. All rights reserved. Keywords: Placode; Development; Nervous system

Introduction The vertebrate head ectoderm contains unique neurogenic regions: the cranial sensory placodes. Like the neural plate, which gives rise to the central nervous system (CNS), placodes are transient columnar, pseudostratified epithelia. They arise at distinct rostrocaudal positions next to the neural tube shortly after the start of neurulation and, because of their ability to generate neurons outside the central nervous system, are excellent model systems to study both inductive interactions and neurogenesis. Placodal cells give rise to the majority of neurons that form the cranial sensory nervous system contributing to the cranial ganglia and the special sense organs associated with hearing, balance,

* Department of Craniofacial Development, King’s College London, Guy’s Hospital, Guy’s Tower Floor 27, St. Thomas Street, London SE1 9RT, UK. Fax: +44 20 7188 1674. E-mail address: [email protected]. 0012-1606/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ydbio.2004.08.037

olfaction and vision. While some placodes are simple neurogenic centres, others such as the otic and olfactory placodes generate a multitude of cell types and undergo complex patterning events once a columnar epithelium has been established. Despite their long history in experimental embryology (the term dplacodesT was coined in 1891 [von Kupffer, 1891]), the importance of placodes for sensory functions and their evolutionary significance as key structures believed to have evolved along with the appearance of higher chordates, placode development has been neglected by modern developmental biologists until very recently. The availability of molecular markers specific for individual placodes as well as for particular cell types derived from them has now stimulated much new research in the field and has lead to exciting findings in placode induction, patterning and cell fate specification. An excellent review has recently summarised in detail the classical and current literature on tissue interactions and signals involved in the induction of individual placodes

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(Baker and Bronner-Fraser, 2001). Here, I will concentrate on some of the earliest steps that initiate placode formation, asking the question of when and how placode induction begins and discussing the evidence for and against the view that all placodes arise from a common placodal field—the pre-placodal region —through a common molecular mechanism.

Cranial placodes: origin of diverse structures and cell types Cranial placodes are regions of columnar epithelium that form between the 10- and 30-somite stage at precise positions along the developing brain (Alvarez and Navascues, 1990; Anniko and Wikstrom, 1984; Bancroft and Bellairs, 1977; Brunjes and Frazier, 1986; Croucher and Tickle, 1989; D’Amico-Martel and Noden, 1983; Hilfer et al., 1989; Mayordomo et al., 1998; Meier, 1978a,b; Mendoza et al., 1982; Romanoff, 1960; Schook, 1980; Van Campenhout, 1956; Wakely, 1976; Fig. 1B). The olfactory placode forms in the anteriormost position next to the forebrain; it gives rise to the olfactory and vomeronasal epithelium including their sensory neurons (Brunjes and Frazier, 1986), to a population of migratory GnRH neurons (Dellovade et al., 1998; SchwanzelFukuda and Pfaff, 1989; Wray et al., 1989) as well as to the glia that will ensheath the olfactory nerve (Chuah and Au, 1991; Couly and Le Douarin, 1985; Norgren et al., 1992). The lens placode forms next to the optic vesicle and is the only cranial placode that does not give rise to neurons; it is included in this review by virtue of its close association with the eye and because like all other placodes, it arises from the ectoderm close to the neural plate. The next more caudal placode is the trigeminal, which occupies a large region next to the mid- and anterior hindbrain and forms the trigeminal ganglion (V) which has somatosensory function and acts as a relay station for stimuli such as temperature, pain and touch from the skin, jaws and teeth. Molecularly, the trigeminal placode can be subdivided into two separate entities: the maxillomandibular and the ophthalmic portions (Baker et al., 1999; Begbie et al., 2002). In fact, in some amphibians two ganglia initially develop and fuse later (Northcutt and Brandle, 1995), while in some lower vertebrates, two distinct ganglia form (Northcutt and Bemis, 1993; Piotrowski and Northcutt, 1996). Caudal to the trigeminal, next to the hindbrain, lies the otic placode; it gives rise to the specialised epithelia of the inner ear, including endolymph secreting cells, supporting cells, sensory hair cells for the detection of sound, balance and acceleration and neurons forming the cochlear– vestibular ganglion (for review, see Brown et al., 2003; Fritzsch et al., 1998, 2002; Rubel and Fritzsch, 2002; Torres and Giraldez, 1998). In fish and aquatic amphibians, it is surrounded by a variable number of pre- and

Fig. 1. Position of the cranial placodes in a 1.5- and 3.5-day chick embryo. (A) At the 10- to 13-somite stage precursors for different placodes are segregated and occupy unique positions in the head ectoderm. Fate maps combined from Bhattacharyya et al. (2004) and D’Amico-Martel and Noden (1983). (B) At 3.5 days of development, all placodes can be recognised morphologically and some have begun to undergo morphogenesis or differentiation. The olfactory placode lies next to the future olfactory bulb, while the lens is surrounded by the retina. The trigeminal placode is situated adjacent to the midbrain, while the otic placode next to the hindbrain has already invaginated to form the otic vesicle. The epibranchial placodes are positioned just dorsal of the branchial clefts.

post-otic lateral line placodes, which develop into mechano- and electroreceptors as well as the neurons that innervate them (Northcutt et al., 1994, 1995; Schlosser, 2002; Schlosser and Northcutt, 2000). These primordia undergo remarkable migration to deposit lines of lateral line organs in the ectoderm of the head and along the entire body axis. Finally, the three epibranchial placodes—geniculate, petrosal and nodose—are located more laterally, just dorsal to the branchial clefts, and form the distal parts of the VII, IX and X cranial ganglia that innervate taste buds, visceral organs and the heart (D’Amico-Martel and Noden, 1983; Schlosser and Northcutt, 2000). It is important to note that all cranial ganglia have a dual origin: while their distal portions are placodal derivatives, their proximal parts are of neural crest cell origin.

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The bplacodal fieldQ hypothesis—support from experimental embryology Despite the structural and functional diversity of sensory organs and cranial ganglia in the adult, it has been suggested that the induction of all placodes begins through a common cellular and molecular mechanism, which involves the formation of a common bplacodal fieldQ—the pre-placodal region (Baker and Bronner-Fraser, 2001; Jacobson, 1963c; Torres and Giraldez, 1998). For such a field to exist two prerequisites have to be fulfilled: first, all placodal precursors should arise from a continuous domain of the embryonic ectoderm and second, this region should have unique properties, being biased or specified towards a placodal fate, accompanied by the expression of a specific set of molecular markers. The idea of a common pre-placodal region has been challenged recently based on developmental and evolutionary considerations (Begbie and Graham, 2001; Graham and Begbie, 2000). First, embryological findings suggested that two types of placodes—the epibranchial and trigeminal—can be induced through different tissue interactions and probably by different signalling molecules in a single step and therefore do not share a common inductive mechanism (Baker et al., 1999; Begbie et al., 1999). However, substantial evidence from both classical and modern experimental embryology indicates that placode induction is a drawn out process that involves a series of events before placodes become committed to their individual fates as exemplified for otic and lens induction (see below for detailed discussion). So far, there is no clear evidence that a specific placode can be induced in a single step from cells that during normal development never contribute to the same or other placodes (see below). Furthermore, the fact that placode dinducingT signals or tissues differ from each other does not argue against a common pre-placodal state as they may represent final triggers that confer placode identity onto cells that are already biased towards a generic placodal fate. Second, while a long-standing view holds that placodes, like neural crest cells, evolved with the emergence of vertebrates (Northcutt and Gans, 1983), structures analogous to the otic and olfactory placodes were recently identified in non-vertebrate chordates based on the expression of molecular markers and the presence of ciliated sensory cells (reviewed in Graham and Begbie, 2000; Holland and Holland, 2001; Manni et al., 2001; Shimeld and Holland, 2000). So far, there is no evidence that lower chordates possess structures homologous to epibranchial placodes, suggesting that these evolved separately from the remaining placodes. It has been argued that their independent emergence during evolution precludes a common molecular mechanism initiating the induction of all vertebrate placodes (Graham and Begbie, 2000). However, it is just as likely that once an ancestral placode developed new placodes could arise by co-option of the same molecular

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pathway, to which additional components were then added to specify the distinct identities of individual placodes. The idea of a common placodal field provides a plausible mechanism by which this could happen: the ancestral placode might have expanded and subsequently subdivided into separate placodes each then acquiring a specific function. In favour of the placodal field hypothesis, histological studies in mouse, fish and some amphibian embryos have revealed a bprimitive placodal thickeningQ that surrounds the anterior neural plate at late gastrula to early neurula stages (Knouff, 1935; Miyake et al., 1997; Platt, 1896; van Oostrom and Verwoerd, 1972; Verwoerd and van Oostrom, 1979). This morphology is maintained in areas where placodes form, while the ectoderm in the non-placode forming regions between them thins out. However, other vertebrate embryos, like the chick, lack these morphological characteristics. Based on previous findings by others and his own experiments in amphibians, Jacobson (1963a,b,c, 1966) was the first to present a concise hypothesis for the complexity of cranial placode induction and the first to suggest the existence of a common pre-placodal region. A large number of studies had determined that the induction of different placodes involves similar tissue interactions: early signals from the endoderm and mesoderm promote the formation of olfactory, lens and otic placodes (otic: Harrison, 1935; Orts-Llorca and Jimenez-Collado, 1971; Stone, 1931; Waddington, 1937; Yntema, 1950; Zwilling, 1940a; see also Gallagher et al., 1996; nasal: Emerson, 1945; Siggia, 1936; Yntema, 1955; Zwilling, 1940b; lens: Jacobson, 1958; Liedke, 1942, 1951, 1955; see also Henry and Grainger, 1987, 1990). These signals, however, are not sufficient to trigger the development of a complete ear or lens vesicle or a nasal sac. Later interactions with specific parts of the CNS seem to complete induction and to confer identity to individual placodes: while the forebrain promotes development of the nasal placode, the optic vesicle promotes lens development and the hindbrain otic placode formation (Haggis, 1956; Harrison, 1920, 1936; Jacobson, 1963a; Reyer, 1958a,b; Street, 1937). Thus, it seems that an initial step common to all placodes involve signals from the mesendoderm, while later, more region-specific signals confer placode-specific properties. In a second series of critical experiments, Jacobson showed that within the ectoderm adjacent to the anterior neural plate, (the PPR) cells are competent to give rise to any placode (Jacobson, 1963c): when future placode territory is rotated along its rostrocaudal axis at open neural plate stages such that the future otic region is now in the position of the olfactory placode and vice versa, placodes develop according to their new position (Fig. 2). However, when rotated later, placode identity seems already determined, but interplacodal tissue remains competent to form new placodes. Thus, at neurula stages, cells within the PPR are able to generate a placode different from their normal fate. These early findings highlight two

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Fig. 2. Diagram of Jacobson’s rotation experiment in amphibians (Jacobson, 1963c). When the placodal domain of an open neural plate stage embryo was rotated along its rostrocaudal axis, placodes developed according to their new position (bottom left). Occasionally an extra otic structure was observed next to the olfactory epithelium. When the same experiment was performed at late neurula stages (bottom right), placode identity was already established and placodes form according to their original fate. Some variation of the results is observed probably due to the exact timing and position of the transplant. Note, however, that even at later stages, inter-placodal ectoderm is still responsive to placode inducing signals and additional placodes are formed close to their normal position, for example, the olfactory placode (diagram lower right). Olfactory: orange; lens: blue; otic: purple.

important features of placode induction: its multi-step nature and a potentially common inducing mechanism for all placode precursors.

Placode induction—a multi-step process Multiple inducing tissues and signals More recent findings clearly support the idea that placode induction is a complex multi-step process. For example, lens induction was initially believed to depend on a single inductive step, in which the optic vesicle instructs the overlying ectoderm to develop into the lens placode (Lewis, 1904, 1907; Spemann, 1901): extirpation of the vesicle led to failure of lens formation, while its ectopic transplantation appeared to induce lens from belly ectoderm. However, soon thereafter conflicting evidence was obtained, showing normal lens formation in the absence of the optic vesicle (King, 1905; Mencl, 1903), and other tissues were implicated in lens induction (Henry and Grainger, 1987; Jacobson, 1958; Liedke, 1942, 1951, 1955). Recent studies using molecular markers and labelling techniques to identify graft and host tissues unequivocally suggest that indeed, early lens induction depends on signals from both the

mesoderm and the young neural plate, either of which alone is insufficient to trigger the formation of a mature lens (Grainger, 1996; Grainger et al., 1988, 1997; Henry and Grainger, 1990; Zygar et al., 1998; for review, see Chow and Lang, 2001). In the absence of the optic vesicle, molecular markers for the presumptive lens ectoderm, like Pax6, are maintained, however, the vesicle is crucial for the ectoderm to acquire placodal morphology as well as for lens maturation as reflected by the expression of lens-specific crystallins and lens fibre formation (Furuta and Hogan, 1998; Kamachi et al., 1998; Li et al., 1994; Porter et al., 1997). Bone Morphogenetic Protein (BMP) and Fibroblast Growth Factor (FGF) signalling have been implicated in mediating some of the interactions between the optic vesicle and the future lens ectoderm to form a mature placode (Faber et al., 2001; Furuta and Hogan, 1998; Wawersik et al., 1999; for review, see Chow and Lang, 2001), but the early signals responsible for setting up the presumptive lens region remain elusive. Induction of the otic placode depends on a similarly complex process: early signals from the mesoderm underlying the placode (Gallagher et al., 1996; Ladher et al., 2000; Mendonsa and Riley, 1999; Orts-Llorca and JimenezCollado, 1971) seem to act in concert with signals from the neural tube to induce otic-specific markers and the otic vesicle. The activity of the paraxial head mesoderm seems to be mediated by FGF signalling, however, depending on the species, different members of the FGF family may be involved (Ladher et al., 2000; Wright and Mansour, 2003; for discussion see Riley and Phillips, 2003). A role for FGF3 as one of the major otic inducers emanating from the hindbrain is conserved among most vertebrates, while the involvement of other FGFs expressed in the hindbrain seems to vary between species (Adamska et al., 2001; Alvarez et al., 2003; Leger and Brand, 2002; Lombardo and Slack, 1998; Mansour, 1994; Maroon et al., 2002; Phillips et al., 2001; Vendrell et al., 2000; Wright and Mansour, 2003). In addition, it has been proposed that in chick hindbrain-derived Wnt signals act synergistically with FGFs to induce the otic placode (Ladher et al., 2000), although this may not be the case in zebrafish (Phillips et al., 2004). While it is clear that otic placode formation requires FGF signalling, loss of function approaches have shown that even in the absence of at least two FGFs, or even most, if not all, FGF signalling, some cells retain otic marker expression and may form a rudimentary otic epithelium (Liu et al., 2003; Maroon et al., 2002; Phillips et al., 2001; Wright and Mansour, 2003). This raises the possibility that additional upstream signals initiating otic development remain to be identified. In contrast, it has been suggested that the trigeminal and epibranchial placodes giving rise to cranial ganglia require less complexity of inductive interactions or signals. One or more unknown signal(s) from the neural tube (no other tissues being required) promote the formation of the ophthalmic part of the trigeminal placode (Stark et al.,

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1997), and epibranchial placodes are generated through an interaction with pharyngeal endoderm, where it comes into contact with the ectoderm just dorsal to the branchial clefts (Begbie et al., 1999). This endoderm expresses high levels of BMP7, and this factor can induce neuronal markers characteristic of epibranchial placodes in isolated, nonepibranchial ectoderm, whereas inhibition of BMP signalling results in the loss of epibranchial neurons. Thus, BMP7 is clearly involved in some step of epibranchial placode specification. However, there is one caveat in interpreting both experiments: the test tissue used to assay placode induction is ectoderm either fated to become the same placode or ectoderm containing precursors for other placodes. It is therefore possible that these tissues had already received other signals at the time of their isolation, which may have established a placodal bias. Placode-specific transcription factors can only induce ectopic placodes within the pre-placodal domain While the studies summarised above focused on the inducing signals and tissues, functional analysis of the transcription factors that integrate these signals within the placode have revealed similar levels of complexity. A large number of transcription factors, among them members of the Sox, Dlx, Fox and Pax gene families, have been identified that are expressed in one or more placodes (for review see Baker and Bronner-Fraser, 2001). While loss-offunction approaches have clearly demonstrated that some of these genes are essential for placode formation, so far gainof-function experiments have failed to identify any factor sufficient to make non-placodal ectoderm (future epidermis) acquire placodal characteristics. The two homeobox genes, Pax6 and Six3, are necessary for normal vertebrate eye and lens development (Carl et al., 2002; Collinson et al., 2000, 2003; Grindley et al., 1997; Hogan et al., 1986; Lagutin et al., 2003; Quinn et al., 1996; Wallis and Muenke, 1999; for review, see: Cvekl and Piatigorsky, 1996; Gehring and Ikeo, 1999; Kawakami et al., 2000; Oliver and Gruss, 1997). Overexpression of either factor results in ectopic lenses, which are, however, always associated with neural structures (either ectopic retinae or a lens that develops very close to the host neural tube; Altmann et al., 1997; Chow et al., 1999; Lagutin et al., 2001; Oliver et al., 1996). Expression of Six3 under the control of regulatory elements that drive Pax2 expression in the otic territory leads to ectopic Pax6 expression in the placode (Lagutin et al., 2001). Likewise, misexpression of the HMG-box factor Sox3 results in the formation of ectopic vesicles that express Pax6, but only next to endogenous placodes (Koster et al., 2000). One of the earliest genes expressed in the otic territory is the forkhead gene foxi1; it is required for otic induction and can induce ectopic expression of the otic marker Pax8 in a spatially restricted manner next to the neural tube, but not in ventral ectoderm (Nissen et al., 2003; Solomon et al., 2003a). Thus, while some

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transcription factors can initiate placode formation, they can only do so near cells that normally give rise to placodes, namely within the pre-placodal region. In summary, the findings described above strongly support the notion that formation of mature placodes is a multi-step process where different tissues and signals act sequentially and/or cooperatively. So far, no experimental manipulation has yet led to the induction of placodes away from their normal position, in ectoderm that does not normally contain placode precursors. Therefore, it is likely that some of the upstream signals that initiate placode formation remain to be identified. Could one of the upstream steps involve the formation of a pre-placodal domain as suggested by Jacobson?

The pre-placodal region is defined by cell fates and unique gene expression The existence of a pre-placodal region implies that all placodal precursors arise from a continuous domain of the embryonic ectoderm. Many of the fate map studies that localised future placodes to the ectoderm and outer neural folds in the head have been performed after neurula stages when precursors for different placodes begin to be confined to unique regions (Fig. 1A; Carpenter, 1937; Couly and Le Douarin, 1985, 1987, 1988; D’Amico-Martel and Noden, 1983; Rfhlich, 1931; for review, see Baker and BronnerFraser, 2001). A recent study in zebrafish shows a continuous domain of placode precursors adjacent to the future brain at gastrula stages (Kozlowski et al., 1997), while lineage studies in the chick have identified a unique region of the embryonic ectoderm that contains precursors for most, if not all, placodes abutting the anterior neural plate slightly later (Bhattacharyya et al., 2004; Streit, 2002; Fig. 3). In this territory, precursors for different placodes are intermingled and are recruited from a large area to their final position (Bhattacharyya et al., 2004; Streit, 2002; Whitlock and Westerfield, 2000). These studies first identify the preplacodal region at early neurula stages surrounding the neural plate from forebrain to hindbrain levels, reminiscent of the bprimitive placodal thickeningQ observed in mouse, fish and some amphibians and of Jacobson’s bplacodal fieldQ. While fate map studies cannot resolve the question of whether or not different placodes share some inductive events, the fact that their precursors initially overlap considerably is consistent with the notion of a pre-placodal region. If a common placode territory indeed exists, it should be characterised not only by the position of relevant precursors, but also by unique properties, like expression of a specific set of molecular markers that distinguish it from other regions of the ectoderm. Indeed, at neurula stages, members of several gene families begin to be expressed or are upregulated in a horseshoe-shaped area encircling the anterior neural plate among them Six, Eya, Id, Dlx, Iro and Fox genes (Akimenko et al., 1994; Esteve and Bovolenta, 1999;

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Fig. 3. Placode precursors at mid-gastrula and early neurula stages. (A) In zebrafish, placode precursors are found in the ectoderm adjacent to the future central nervous system (grey) from fore- to hindbrain level. Precursors for different placodes partially overlap, but are roughly organised according to their later position along the rostrocaudal axis. Vermillion: lens and olfactory placode, telencephalon; pale yellow: lens, olfactory epithelium, anterior cranial ganglia, otic vesicle, telencephalon; green: otic vesicle, posterior lateral line; dark grey: caudal lateral line; modified according to (Kozlowski et al., 1997); CNS fate map after (Woo and Fraser, 1995). (B) At the 0–1 somite stage in the chick, precursors for different placodes are intermingled in a horseshoe-shaped domain encircling the neural plate. Their posterior limit lies at the level of Hensen’s node adjacent to cells that will contribute to rhombomeres 6–7. Olfactory: orange; lens: blue; otic: purple; epibranchial: dark blue. Note: complete maps for epibranchial and trigeminal precursors are not available. Modified after Bhattacharyya et al. (2004) and Streit (2002).

Kee and Bronner-Fraser, 2001a,b; Liu and Harland, 2003; Luo et al., 2001a,b; McLarren et al., 2003; Mishima and Tomarev, 1998; Nissen et al., 2003; Ohyama and Groves, 2004; Pandur and Moody, 2000; Papalopulu and Kintner, 1993; Pera et al., 1999; Sahly et al., 1999; Schlosser and Ahrens, 2004; Solomon and Fritz, 2002; Solomon et al., 2003b; Streit, 2002; Wilson and Mohun, 1995). Some of them, like Dlx genes, are not uniquely found in placodal cells but also encompass other ectodermal derivatives like future epidermis and/or neural crest. In contrast, Six and Eya gene expression domains most closely reflect the location of placode precursors (compare Figs. 3 and 4) and members of both families have been described in comparable patterns in chick, fish and amphibian embryos (Esteve and Bovolenta, 1999; McLarren et al., 2003; Mishima and Tomarev, 1998; Pandur and Moody, 2000; Sahly et al., 1999; Schlosser and Ahrens, 2004; Streit, 2002). Although Xenopus fate map data for the non-neural ectoderm at this stage are not available, a comparative expression analysis of placodal transcription factors relative to those found in neural and neural crest ectoderm supports the notion that Six and Eya genes may represent pre-placodal markers (Schlosser and Ahrens, 2004). During later development, most of the genes present in the placodal territory are either lost completely from placodal tissue, maintained in only some placodes (e.g., Fox) or down-regulated before re-appearing later in some mature placodes (e.g., Dlx). In contrast, mimicking morphological changes of the ectoderm during placode formation (see above), Six and Eya are the only transcripts to be maintained in all developing placodes, while being lost from inter-placodal domains.

Thus, the position of placode precursors is demarcated by co-expression of a specific set of genes in a continuous domain surrounding the rostral neural plate, strongly supporting the idea that different placodes initially share a developmental programme. It is conceivable that cells within this region have received signals to bias them towards a placodal fate, which in turn may account for the fact that induction of ectopic placodes has so far only been achieved close to their normal position (see above). The precise function of Six and Eya proteins during these processes is still unclear, however, it is possible that they specify cells as placodal without conferring placodal identity. While several studies have addressed specification of individual placodes, we know nothing about the developmental state of pre-placodal cells. However, it is clear that this territory is unique due to its restriction to specific cell fates, its special properties and the expression of a unique set of molecular markers.

The Six/Eya/Dach network in the pre-placodal region Among the many genes expressed in the pre-placodal region, the expression of members of the Six and Eya families most closely mirrors the cellular changes during placode formation. Their Drosophila homologues, sine oculis (so) and eyes absent (eya), form a regulatory network that, together with the nuclear factor dachshund (dac), controls specification of sensory structures, namely photoreceptor cells (Bonini et al., 1993, 1997; Chen et al., 1997; Li et al., 2003; Mardon et al., 1994; Pignoni et al., 1997; Shen

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Fig. 4. Expression of pre-placodal markers. Whole mount in situ hybridisation of 3–5 somite chick embryos using Six1 (A, aV), Eya2 (B, bV) and Dach1 (C, cV) antisense probes. Six1 (A, aV) and Eya2 (B, bV) expression in the ectoderm is confined to a domain surrounding the neural plate (np) from its most anterior edge to approximately node levels (arrow in A–C). This region corresponds to the position of placodal precursors, the pre-placodal domain (ppr; see Fig. 3). In contrast, Dach1 transcripts (C, cV) are distributed more widespread and found in the neural plate (np) as well as the pre-placodal domain (ppr), where they overlap with Six1 and Eya2.

and Mardon, 1997; for review, see: Kumar and Moses, 2001c). Mutations in any of these genes leads to absence or reduction of the Drosophila eye, while their overexpression can induce ectopic eye formation in a spatially restricted manner (Bonini et al., 1993; Mardon et al., 1994; Pignoni et al., 1997). In vertebrates, members of these families are not only expressed in the pre-placodal domain, but also later in different combinations in each of the mature sensory placodes and some of their derivatives (for review, see Hanson, 2001; Kawakami et al., 2000). For example, while Eya1, Six1, Six4 and Dach1 are found in parts of the otic vesicle, the olfactory placode expresses Eya2, Six1 and Six3 (Bovolenta et al., 1998; Davis et al., 1999; Ghanbari et al., 2001; Heanue et al., 2002; Mishima and Tomarev, 1998; Oliver et al., 1995; Pandur and Moody, 2000; Xu et al., 1997). In addition, loss-of-function analysis has revealed an important role for Six and Eya proteins in ear, eye and nasal development. Mice heterozygous for Eya1 show a conductive loss of hearing due to defects of the middle ear (Xu et al., 1999), a condition very similar to the human Branchio-Oto-Renal syndrome caused by a mutation in the EYA1 gene (Abdelhak et al., 1997). Homozygous Eya1 / mice display severe inner ear defects: otic placode formation is initiated normally but development arrests at the vesicle stage and the cochlear–vestibular ganglia do not form (Xu et al., 1999). In addition, the epibranchial placode derived petrosal ganglia are missing. Mutations in the human EYA1 gene also lead to congenital eye defects (Azuma et al., 2000), however, the eye phenotypes in mice have been less well studied. Mice lacking Six1 function

display inner ear abnormalities similar to the defects observed in Eya1 / mice: the otic vesicle fails to grow and the cochlear duct and/or semicircular canals are absent (Laclef et al., 2003; Li et al., 2003; Zheng et al., 2003). Like Eya1 mutant mice, Six1 / mice lack both the cochlear– vestibular and petrosal ganglia. However, a complete loss of placodal derivatives in any of the mutants generated has not been observed as one might have expected if these genes were instrumental in defining the pre-placodal domain. Since several members of the Six and Eya families are co-expressed in this region and seem to share functional properties, the lack of an early phenotype may be due to functional redundancy. There is good evidence that Six, Eya and Dac proteins form a regulatory network and that they interact physically to activate downstream target genes. In Drosophila, so, eya and dac expression is interdependent, while their combined misexpression in imaginal discs other than the eye disc shows strong synergistic effects with a dramatically increased frequency of ectopic eye induction (Chen et al., 1997; Mardon et al., 1994; Pignoni et al., 1997; Shen and Mardon, 1997). Although the interdependence of gene expression in vertebrates is not always conserved (Heanue et al., 2002; Zheng et al., 2003; for review see: Hanson, 2001; Wawersik and Maas, 2000), the only case where compound homozygous mutations have been generated in mice, namely for Six1 and Eya1, shows a more severe ear phenotype than each mutation separately (Li et al., 2003; Zheng et al., 2003), supporting the idea that they may act in a molecular network and synergise with each other. In addition, in vitro studies have clearly demonstrated a

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physical interaction between Six and Eya as well as Dach and Eya proteins (Chen et al., 1997; Ikeda et al., 2002; Li et al., 2003; Ohto et al., 1999; Silver et al., 2003). While Six1 alone or Six1/Dach seems to act as transcriptional repressors, Eya recruits co-activators; due to their phosphatase activity, Eya proteins stabilise co-activator interactions and switch the complex to activate downstream target genes (Li et al., 2003). Thus, co-expression of Six, Eya and Dach family members in the pre-placodal domain may be functionally significant and their role will need to be addressed in the future. In the Drosophila eye, the Six/Eya/Dach network functions downstream of the Pax6 homologue eyeless (ey), while in other embryonic tissues, their expression is independent of Pax genes (Bonini et al., 1997; Halder et al., 1998; Kumar and Moses, 2001b; Niimi et al., 1999). Interestingly, during vertebrate placode development, Pax gene expression (with the exception of Pax6 in the lensolfactory domain; Bhattacharyya et al., 2004; Li et al., 1994) is only initiated once placodes with characteristic identity begin to be specified. While Pax6 identifies the lens and later the olfactory placode (Grindley et al., 1995; Li et al., 1997; Nornes et al., 1998; Schlosser and Ahrens, 2004; Walther and Gruss, 1991), Pax2 is specific for the otic and epibranchial (Groves and Bronner-Fraser, 2000; Heller and Brandli, 1999; Krauss et al., 1991; Pfeffer et al., 1998; Schlosser and Ahrens, 2004) and Pax3 for the trigeminal placode (Stark et al., 1997). So far none of the Pax genes seems to be expressed in the lateral line placodes of amphibians and fish embryos (Schlosser and Ahrens, 2004). It is therefore tempting to speculate that the expression of members of the Six/Eya/Dach network in the pre-placodal domain assembles some of the molecular network required for placode formation, but is not sufficient by itself to complete the developmental programme. In this scenario, Pax gene expression may initiate the formation of a placode proper and together with other transcription factors confer placode identity. Thus, one potential role of the Six/Eya/Dach network is to bestow placodal competence or bias to the ectoderm next to the anterior neural plate. A quite different possibility, however, is that the Six/Eya/ Dach network is involved in regulating proliferation of preplacodal cells. Loss-of-function alleles of so, eya and dac in Drosophila produce a transient overgrowth within the eye field, followed by extensive cell death resulting in reduction or loss of the eye. In vertebrates, in vivo and in vitro data suggest that lack of functional Six1, Eya2 or Eya3 leads to reduced proliferation (Li et al., 2003; Pignoni et al., 1997; Zheng et al., 2003). As a consequence, Six1 as well as Eya1 mutant mice show severe inner ear phenotypes displaying small otic vesicles that lack several otic placode-derived structures or cell types. Regardless of the precise molecular function of the Six/ Eya/Dach network, it is remarkable that the same molecular cassette used in Drosophila to specify photoreceptor cells

has been conserved in vertebrates to regulate sensory organ development at different levels.

Signals and tissues mediating the induction of the pre-placodal domain How is the pre-placodal region established in the ectoderm adjacent to the rostral neural plate? As mentioned at the beginning of this review, studies in amphibian embryos have implicated the endoderm, the presumptive heart mesoderm and the neural plate as early placode inducing tissues, which may act in combination or sequentially. Neither mesoderm nor endoderm alone, however, appears to be sufficient to trigger the development of a complete ear or lens vesicle or a nasal sac. Signals emitted by these tissues may be responsible for setting up the initial common placodal field. Neural crest cells arise at the border of the neural plate in close association with future placodes. Interaction of the neural plate with future epidermis is sufficient to induce neural crest at the interface (Dickinson et al., 1995; Mancilla and Mayor, 1996; Moury and Jacobson, 1990; Selleck and Bronner-Fraser, 1995) and both Wnt and BMP pathways have been implicated in this process (for review, see: Aybar and Mayor, 2002; Knecht and Bronner-Fraser, 2002; LaBonne, 2002; Mayor and Aybar, 2001; Nieto, 2001; Yanfeng et al., 2003). Are the same tissue interactions and signalling pathways responsible for placode induction? In Drosophila, the expression of so, eya and dac during eye development is dependent on the presence of the BMP homologue decapentaplegic (dpp) (Chen et al., 1999; Curtiss and Mlodzik, 2000), while in the leg imaginal disc dac is induced by a combination of dpp and the Wnt homologue wingless (Wg) (Lecuit and Cohen, 1997). It will be interesting to investigate whether similar upstream signalling pathways control pre-placodal gene expression. Some support for this idea comes from the finding that BMPs participate in patterning the ectoderm during or shortly after gastrulation (for review, see: Mayor and Aybar, 2001; Sasai and De Robertis, 1997; Wilson and Hemmati-Brivanlou, 1997). BMPs are thought to act as a morphogen gradient to specify different cell types at distinct concentrations: high levels of BMP activity promote the formation of epidermis, intermediate levels the formation of neural crest, while low or no BMP signalling allows neural development (Barth et al., 1999; Nguyen et al., 1998, 2000; Tribulo et al., 2003; Wilson et al., 1997). A recent study revealed that expression of the homeodomain protein Iro1, which labels the preplacodal region, is regulated by BMP (Glavic et al., 2004). However, the formation of olfactory and otic placodes is differentially affected in zebrafish mutants that show moderate or severe disruption of the BMP signalling pathway (Nguyen et al., 1998), making it unlikely that a unique threshold of BMP defines the placode territory. Future studies will be necessary to unravel the signalling

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pathways that specify the pre-placodal region and to determine how these are integrated with signalling mechanism that define the position of individual placodes.

Transcription factor codes for different ectodermal domains? One important question that remains open is how ectodermal patterning signals are interpreted by individual cells to implement cell fate decisions. Some of the earliest patterning events appear to begin before gastrulation, as indicated by the complex domains of gene expression in the ectoderm. Evidence from the chick suggests that before primitive streak formation the ectoderm is subdivided into two domains revealed by the mutually exclusive expression of Sox3 and ERNI in one (Streit et al., 2000) and low levels of Msx1 (Streit and Stern, 1999), Dlx5 (Pera et al., 1999) and Gata2 and -3 (Sheng and Stern, 1999) in the other. Concomitant with the onset of expression of stable neural markers, like Sox2, in the future neural plate, Msx1 and the early neural crest marker Pax7 are up-regulated along its border in a fairly broad stripe of cells. At the same time, preplacodal gene expression starts in the ectoderm lateral to the neural plate, overlapping medially with Msx1 and Pax7 (Streit and Stern, 1999; Litsiou and Streit, unpublished observations). Shortly thereafter, however, early crest and placodal markers are restricted to distinct regions of the ectoderm: Msx1 and Pax7 are confined to the neural folds abutting Sox2 medially and Six1, Six4 and Eya2 laterally (McLarren et al., 2003; Schlosser and Ahrens, 2004; Streit, 2002). The successive restriction of transcription factors to distinct ectodermal domains may reflect the specification of different cell fates within the embryonic ectoderm. In addition, these observations may point to negative as well as positive regulatory relationships between different transcription factors, which cooperate to integrate ectodermal patterning signals on a cell-by-cell basis.

Cell movements within the pre-placodal domain Once the pre-placodal domain is established, how do precursors for individual placodes acquire distinct properties and become different from each other? Within the preplacodal ectoderm, precursors for different placodes are initially interspersed (Bhattacharyya et al., 2004; Kozlowski et al., 1997; Streit, 2002). Precursors for specific placodes are recruited from a large area within this territory and converge to their final position. Recent studies both in zebrafish and chick suggest that they do so by extensive cell movements while constantly changing their neighbours and undergoing cell rearrangements (Streit, 2002; Whitlock and Westerfield, 2000). In the chick, groups of cells from a single location ultimately contribute to different placodes. How is their segregation controlled? One possibility is that

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these movements are random and that only cells that encounter placode-specific inducing signals from surrounding tissues are directed towards a specific fate. Alternatively, individual cells or groups of cells may already have acquired specific identities and according to these properties move directionally to their final destination, sorting out from their neighbours. Interestingly, some placode-specific genes like the otic marker Pax2 begin to be expressed in a salt-and-pepper pattern (Streit, 2002). Thus, mosaic gene expression may reflect differential properties of individual cells in the pre-placodal territory. It will be necessary in the future to investigate whether directional cues guide these precursors to their target position in the mature placode and the degree to which these mosaic patterns of expression might reflect differential competence to inducing signals, or different states of commitment and differential responsiveness to chemoattractants and/or repellents, or cell sorting mechanisms that would guide them to their appropriate destinations.

Parallels between fly and vertebrates: determination of placode and imaginal disc identity Although vertebrate sensory placodes have no direct structural or functional homologues in Drosophila and are unlikely to have evolved directly from sensory organs in the fly, some of the molecular cassettes that regulate the development of such organs in both groups are surprisingly well conserved. The idea of a common domain for sensory placode precursors is remarkably similar to the situation in Drosophila, where light, odour and sound perceiving cells arise from a common primordium, the eye-antennal disc. In the adult, photoreceptor cells are confined to the compound eye, while the antenna contains cells with both auditory and chemosensory function. Precursors for these cells arise from the eye-antennal disc, a small group of epithelial cells that is set aside during early development. During larval development eye and antennal precursors segregate until two separate entities are established that have distinct identities: the eye and the antennal primordium. Some of the key regulators that confer identity to these primordia are the transcription factors distalless and eyeless (Cohen et al., 1989; Dong et al., 2000; Halder et al., 1995, 1998; Sunkel and Whittle, 1987; for review, see Gehring, 1996; Panganiban and Rubenstein, 2002). Both proteins are initially coexpressed, but subsequently separate with eyeless being confined to the eye primordium, while distalless is found in the antennal part (Kumar and Moses, 2001a,b). It has been suggested that both transcription factors negatively cross regulate each other to establish eye versus antennal cell fates (Kurata et al., 2000). Interestingly, a similar molecular mechanism may be involved in conferring lens versus olfactory placode identity in vertebrates. It is well established that the vertebrate eyeless homologue, Pax6, is required in the presumptive lens ectoderm for development

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of a normal lens placode and a functional lens (AsheryPadan et al., 2000; for review, see Ashery-Padan and Gruss, 2001; Callaerts et al., 1997; Gehring, 2002). Before placode formation, however, Pax6 is expressed in the anterior ectoderm encircling the future forebrain—a region of the ectoderm that contains cells fated to become lens and olfactory placode (Bhattacharyya et al., 2004; Li et al., 1994). Interestingly, the distalless homologue Dlx5 initially colocalises with Pax6 in the ectoderm, however, as soon as the lens placode forms a columnar epithelium, Dlx protein is lost form this territory, while Pax6 expression is maintained (Bhattacharyya et al., 2004). When lens precursors are forced to maintain Dlx5 beyond this time, they become excluded from the lens, cluster in the non-lens ectoderm and acquire lens-specific gene expression (Bhattacharyya et al., 2004). These data suggest that the loss of Dlx protein is required for cells to acquire lens identity in a process that parallels molecular events that lead to the manifestation of imaginal disc identity in the fly. What is the cellular mechanism underlying this behaviour? Like Dlx5 maintaining lens precursors, Pax6 / cells in mouse chimaeras are excluded from the lens territory (Collinson et al., 2000), suggesting that Pax6 expression confers cells with adhesive properties different from their neighbours. Similarly, in the leg imaginal disc of Drosophila dll / clones sort out from their dll+/+ neighbours displaying apparent differential adhesion (Gorfinkiel et al., 1997; Wu and Cohen, 1999; for review, see Panganiban and Rubenstein, 2002). Interestingly, differential expression of cell adhesion molecules is observed during lens placode formation in the mouse: placode cells acquire Ncadherin expression while concomitantly losing P-cadherin (Xu et al., 2002). Together, these findings raise the possibility that during vertebrate placode formation, a cell sorting mechanism acts to ensure that only cells with appropriate gene expression profiles are included in the developing placode, while those that do not conform with their neighbours are excluded. Future experiments will need to address whether adhesive properties of placodal cells are under direct or indirect control of transcription factors like Pax6 and Dlx5. Thus, despite their developmental and structural differences, there is a surprising similarity in how cells contributing to sensory organs are established in the fly and vertebrates. Not only are the same molecular networks deployed to specify identity, but they may also act to segregate precursors destined to contribute to different sensory structures.

Conclusion In summary, it is evident that placode induction is a complex process that involves signals emanating from different tissues and which act sequentially and/or in parallel to bestow individual identity to each sensory placode.

Precursors for different placodes arise from a common preplacodal region characterised by the expression of a unique set of molecular markers and by unique cellular properties. Future studies will have to investigate the upstream signals that establish the pre-placodal region as well as the role of transcription factor networks implementing cell fate decisions within this region. Molecular networks that govern sensory organ formation in insects are remarkably conserved in vertebrates and may be used repeatedly to control specification of the pre-placodal field, placode identity as well as cell type specification within placodes.

Acknowledgments I am grateful to Claudio D. Stern for critical reading of the manuscript and would like to thank the anonymous reviewers for their particularly constructive comments.

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